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Camelpox: A brief review on its epidemiology, current status and challenges
Acta Tropica 158 (2016) 32–38
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Acta Tropica journal homepage: www.elsevier.com/locate/actatropica
Camelpox: A brief review on its epidemiology, current status and challenges Shyam Singh Dahiya a,∗ , Sachin Kumar b , Sharat Chandra Mehta a , Shirish D. Narnaware a , Raghvendar Singh a , Fateh Chand Tuteja a a b
National Research Center on Camel, Jorbeer, Bikaner, Rajasthan 334001, India Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
a r t i c l e
i n f o
Article history: Received 17 December 2015 Received in revised form 12 February 2016 Accepted 18 February 2016 Available online 20 February 2016 Keywords: Camelpox Zoonosis Outbreak Vaccine Immune evasion
a b s t r a c t Camelpox caused by a Camelpox virus (CMLV) is a very important host specific viral disease of camel. It is highly contagious in nature and causes serious impact on health even mortality of camels and economic losses to the camel owners. It manifests itself either in the local/mild or generalized/severe form. Various outbreaks of different pathogenicity have been reported from camel dwelling areas of the world. CMLV has been characterized in embryonated chicken eggs with the production of characteristic pock lesions and in various cell lines with the capacity to induce giant cells. Being of Poxviridae family, CMLV employs various strategies to impede host immune system and facilitates its own pathogenesis. Both live and attenuated vaccine has been found effective against CMLV infection. The present review gives a comprehensive overview of camelpox disease with respect to its transmission, epidemiology, virion characteristics, viral life cycle, host interaction and its immune modulation. © 2016 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Global scenario . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Virion and genome characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Viral life cycle and viral proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Camelpox pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Host-CMLV interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Immune response and vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
1. Introduction Camelpox is a highly contagious disease of camels with an exception of dromedary camel in Australia and tylopods (llama and related species) in South America (Mosadeghhesari et al., 2014; Pfeffer et al., 1998; Wernery and Kaaden, 2002). The disease can cause high mortality and morbidity in camels leading to greater
∗ Corresponding author. E-mail address: [email protected] (S.S. Dahiya). http://dx.doi.org/10.1016/j.actatropica.2016.02.014 0001-706X/© 2016 Elsevier B.V. All rights reserved.
economic impact in the countries like India and Middle East. The camelpox causes higher mortality in young animals than in adults (Kriz, 1982). The disease can manifest itself in two distinct forms, i.e. milder and localized in old camels or severe and generalized in young camels which may cause heavy mortality (Wernery and Kaaden, 2002). The disease causes a decrease in milk production in lactating animals, weight loss and debilitating condition in all the infected animals (Kinne et al., 1998). Outbreaks have often been attributed to weaning or poor nutrition, which may sometimes result into severe fatality (Bhanuprakash et al., 2010a). Since 1978, the smallpox vaccination has been stopped and the concern has been shown as the human population has become susceptible
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to emerging or re-emerging of any virus from the poxvirus group (VARV, monkeypox, CMLV or taterapox virus) (Gubser and Smith, 2002). Camelpox is important not only to control the economic losses in camel rearing areas (Otterbein et al., 1996) but to deal with it in a logistic and holistic approach to check its spread to other nearby areas also (Bhanuprakash et al., 2010a). Present review gives a comprehensive overview of camelpox disease with respect to its epidemiology, mode of transmission, virion characteristics and its immune modulation. 2. Global scenario In the list of many primordial viral infections known to mankind, poxviruses have its own important place among the most feared viruses of livestock animals and humans (Essbauer et al., 2009). As per the United Nation Food and Agriculture Organization, there are approximately 20 million camels in the world (http://faostat.fao. org). Camelpox was first reported from the Punjab province in India in the year 1909 (Wernery and Kaaden, 2002). Camelpox incidences have been reported from the Middle East, Asia, Africa, Southern Russia and India (Sharawi et al., 2011; Wernery and Kaaden, 2002). OIE has declared camelpox as a reportable disease (Bray and Babiuk, 2011). Sporadic outbreaks of camelpox occur in the camel dwelling areas and their incidences increases seasonally especially, during the rainy season (Anonymous, 2008). From an economic point of view, camelpox is possibly the most important orthopoxviral disease (Azwai et al., 1996). In camel rearing countries, camel provides a mode of transport, milk, meat and wool for both nomadic as well as non-nomadic people (Duraffour et al., 2011b). The presence of camelpox in the camel herd has great significance because of its economical impact over the camel owners (Bett et al., 2009; Pfeffer et al., 1998; Wernery and Kaaden, 2002) in terms of loss of health condition, secondary infections, loss of weight and milk production (Duraffour et al., 2011b). Moreover, camelpox is considered important in camel trade and is viewed carefully in order to avoid its transmission to the adjacent camel harbouring countries (Bhanuprakash et al., 2010a). Further, death of the camel by camelpox deprives camel owners of their milk and makes camel calf undernourished which brings greater threat to dreadful diseases and higher infant mortality (Kriz, 1982). Camelpox has been designated as very contagious and extremely transmissible skin disease of camels. CMLV and variola virus (VARV)—causative agent of smallpox, share genome co-linearity and are also unique in infecting a single host species (Fenner, 1989). Exploring the genomics and biological aspects of CMLV can help us to understand the VARV (Duraffour et al., 2011b) as there is a possibility of smallpox-like disease in some immune-compromised human population following its infection (Baxby, 1975). 3. Epidemiology Housawi, (2007) demonstrated CMLV specific antibody prevalence rate of 0%, 6% and 10% in cattle, sheep and goat respectively, in Saudi Arabia (Housawi, 2007). Based on these results, Duraffour et al., suggested the potential adaptation of camelpox in enzootic areas to hosts other than camel (Duraffour et al., 2011b). CMLV is host specific and isolated reports of some skin lesions in humans have been reported (Bera et al., 2011; Ramyar and Hessami, 1972). The movement of large animal herds facilitates the continued propagation of CMLV. Arthropod vector may also help in propagating the infection and the virus may get transmitted directly from infected camel by skin injuries or through inhalations (Anonymous, 2008; Bera et al., 2011). CMLV has been isolated from the camel tickHyalomma dromedarii harboring camelpox infection (Pfeffer et al., 1996). CMLV may get into the body secretions including milk and
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may survive in the dried scab for as long as four months. CMLV was confirmed in the skin of the camels through PCR and on the CAM of specific-pathogen-free (SPF) embryonated chicken eggs (ECE) even after one year of their previous infection (Yousif and Al-Naeem, 2012). The incubation period of camelpox varies from 3 to 15 days (Anonymous, 2008; Moss, 2007). Depending upon the virus strain, the infection may range from a mild type of skin lesions to moderate and serious systemic infections (Wernery and Kaaden, 2002). Moreover, pregnant animals may abort and the animal dies due to secondary infections and septicaemia (Kriz, 1982). The morbidity rate depends upon the circulation of the virus in the herd (Wernery and Kaaden, 2002). The incidence of camelpox is more in the male camels as compared to the female counterpart while the mortality is higher in the young ones than in the adults (Kriz, 1982). The disease is often associated with poor nutrition (Bhanuprakash et al., 2010a). Besides other factors, the virus gets transmitted from infected to healthy camel through shared animal husbandry practices.
4. Virion and genome characteristics The etiological agent of camelpox disease in camels is an epitheliotropic DNA virus (Salem et al., 2008). It is a member of the genus Orthopoxvirus (OPV) under subfamily Chordopoxvirinae and the family Poxviridae (Essbauer et al., 2009). The brick shaped virion is 265–295 nm in size and surrounded by an outer membrane studded with irregularly arranged tubular proteins (Moss, 2007). CMLV replicates in the cytoplasm and carries a large number of viral encoded enzymes, associated within the virion. CMLV is ether resistant and chloroform sensitive (Moss, 2007). CMLV remained unaffected between a pH range of 3–8.5 for one hour and resists heat at 56 ◦ C for one hour; however, its infectivity com◦ pletely disappeared at 70 C after 30 min (Falluji et al., 1979). The genome of CMLV is composed of a single linear double-stranded DNA molecule of 205,719 bp and contains 211 putative genes (Afonso et al., 2002). The genome of CMLV consists of a central region bound by identical inverted terminal repeats of approximately 7 kbp. Although the genome of CMLV shares close structural and functional similarities with other OPVs, it contains unique region of about 3kbp encoding for three ORFs (CMLV185, CMLV186, CMLV187) which are absent in other OPVs (Afonso et al., 2002). The genes in the middle of the orthopoxviruses genome are conserved while towards either terminal are variable, which encodes proteins involved with host tropism, virulence or immunomodulation (Gubser and Smith, 2002). Based on nucleotide sequence analysis, the CMLV is most closely related to VARV. The CMLV-CMS ITR just like variola virus encodes proteins within 650 bp of its terminus (Massung et al., 1994; Shchelkunov et al., 1995, 2000). At nucleotide level, CMLV and VAR shares 96.6–98.6% identity. The DNA distance matrix also showed lower genetic distance between CMLV and VAR than between CMLV and vaccinia virus. The percentage amino acid identity of CMLV with other poxviruses showed that CMLV is more closely related to VAR than any other viruses. The camelpox genome is composed of 66.9% A + T and has a distinctive Hind III restriction map (Gubser and Smith, 2002). Till date about 45 serotypes have been reported for CMLV and three serotypes (CMLV1, CMLV2 and CMLV-Hyd 06) are more prevalent in Indian subcontinent while serotypes 19 and 16 are prevalent in the Middle East and Africa respectively. These strains have different physicochemical properties and manifest themselves differently in various cells and in embryonated chicken eggs (Duraffour et al., 2011b).
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5. Viral life cycle and viral proteins Unlike other DNA viruses, poxviruses rely mostly on the virusencoded proteins for their replication in the cytoplasm (Moss, 2007, 2012). Most of the information regarding the poxvirus replication has been deduced utilizing vaccinia virus as a model in mammalian cells (Buller and Palumbo, 1991). The mature virion enters either by fusing with the host cell by interacting with glycosaminoglycans at the cell surface or with the endosomal membrane (White et al., 2008). Although poxviruses have not been reported for any single receptor mediated adsorption to the cell (Buller and Palumbo, 1991), 11–12 proteins are enlisted for its post-attachment entry (Moss, 2012). CMLV fuses with the host cell membrane and releases as an extracellular enveloped virion (EEV/EV) (Smith et al., 2002; Ward and Moss, 2001). The uncoating of the poxvirus starts with the loss of virion proteins and lipid (Dales, 1965) followed by loss of its core membrane (Holowczak, 1972; Sarov and Joklik, 1972). Deterrence of uncoating has been reported by the inhibition of transcription or translation indicating that either the virus induced or its encoded proteins are required for its uncoating (Joklik, 1964), About 50% of the transcripts get capped and polyadenylated once the core (containing DNA, viral encoded enzymes and early transcriptional factor) of the virus reaches the cytoplasm (Kates and Beeson, 1970; Kates and McAuslan, 1967; Moss, 1990). Virus encoded DNA polymerase, thymidine kinase, thymidylate kinase ensure availability of DNA for its replication. Vaccinia virus encoded proteins like virus growth factor and complement-binding protein deal with its spread and blocks classical complement pathway by binding with C4b, respectively (Buller et al., 1988a, 1988b; Kotwal et al., 1990; Stroobant et al., 1985). Poxvirus replication occurs in the cytoplasm at specific site known as viroplasm (Buller and Palumbo, 1991). The high level of recombination in the poxvirus infected cells promoted evolution and gain of beneficial functions which facilitate the multiplication and its transmission without causing premature mortality of the host (Buller and Palumbo, 1991). DNA replication is followed by intermediate and late classes of mRNA and protein synthesis (Moss, 2012). Virus packaging and its release as a mature virion (MV) with single external membrane or as a wrapped virion (WV) with triple membrane takes place after the expression its late genes (Cyrklaff et al., 2005; Heuser, 2005; Hollinshead et al., 1999). MVs are assumed to facilitate spread between the host while EVs are believed to mediate spread within the host (Moss, 2012). Depending upon the poxvirus and infected cell, the virion may exit through microvilli (Ichihashi et al., 1971) or Golgi apparatus (Dales and Pogo, 1981). Poxvirus can acquire its envelope from a vacuole (Purcell et al., 1972) and released from cell through non-membrane-bound vacuoles (Sutton and Burnett, 1969) or by A-type inclusion body (Ichihashi and Matsumoto, 1966; Ichihashi et al., 1971). CMLV encodes 211 putative genes encoding various proteins of length 53–1869 amino acids long. CMLV encodes for similar proteins as those present in other orthopoxvirus viz. proteins associated with virion core, intracellular mature virus (IMV), enzymes associated with protein modification, DNA packaging and release of Extracellular enveloped virion (EEV) (Afonso et al., 2002). Some of the viral proteins having a pivotal role in immune evasion, determining host range and virulence are summarized in Table 1.
lence. Following 1–3 days of fever and lymph nodes enlargement, skin lesions appear starting from erythematous macules, papules, vesicles and finally into a pustules (Ayelet et al., 2013). The lesions appear first on the head and then progresses to the rest of the body parts (Fig. 1). In systemic form, the disease prognosis is usually grave, the signs include anorexia or diarrhoea and the lesion may appear on the mucous membrane of mouth respiratory and digestive tract. Histopathologically, the lung lesions are consolidated with expanded alveoli and a small number of diphtheroid lesions in the tracheal mucosa (Kinne et al., 1998). In pulmonary lesions, the initial lung lesions have been shown to contain hydropic degeneration and infilteration of affected areas by macrophages with foci of proliferative alveolitis and bronchiolitis. Histopathological examination of lung shows foci of proliferated bronchial epithelium, necrosis and fibrosis (Kinne et al., 1998). Histopathology of the skin lesions from free-ranging camels suggestive of camelpox have been reported to display significant acanthosis with degeneration of acanthocytes. In addition, hyperkeratosis and dermal layer infiltrated with inflammatory cells mainly neutrophils along with dermal fibroplasias has also been reported (Motalab and Ahmed, 2014). Chorioallantoic Membrane (CAM) route has been employed by various researchers to isolate CMLV in 11–13 day old ECE. The grayish white pock lesions can be observed in eggs infected with CMLV five days post inoculation (Al-Zi’abi et al., 2007; Davies et al., 1975; Duraffour et al., 2011b; Falluji et al., 1979; Sheikh Ali et al., 2009; Yousif and Al-Naeem, 2012). Numerous cell lines of different origin have been utilized successfully to culture CMLV. In general, cell lines derived from camel, monkey, chicken, lamb, calf, horse, human, hamster, mouse and dog support one or another strain of CMLV (Duraffour et al., 2011b). Usually, the cells infected with CMLV show characteristic CPE in the form of rounding and ballooning of cells, micro-plaque formation, cytoplasmic elongation, and syncytia formation (Al-Zi’abi et al., 2007; Ayelet et al., 2013; Bhanuprakash et al., 2010a; Davies et al., 1975; Duraffour et al., 2011b; Falluji et al., 1979; Mosadeghhesari et al., 2014; Sheikh Ali et al., 2009). The exploration of other species as an alternative host for CMLV has not been encouraging in rabbit, mice, cattle, sheep, goat, guinea pig, rats, hamsters and chickens (Bhanuprakash et al., 2010a; Davies et al., 1975; Falluji et al., 1979; Ramyar and Hessami, 1972). CMLV infection of athymic nude mice via the intranasal route has been reported to result in failure to gain body weight while its intracutaneous infection resulted in the disseminated lesions. It is interesting to note that cells originated from human have been utilized to carry out CMLV based studies (Duraffour et al., 2007). Davies et al. have reported the development of ulcers on the lips and mouth of the people consuming milk from the camelpox affected camels in Northern Kenya (Davies et al., 1975). Although CMLV could not be isolated from any of the human subjects, three cases have been reported from India which were confirmed by counter immunoelectrophoresis (CIE); serum neutralization test (SNT); plaque-reduction neutralization test (PRNT), indirect immunoperoxidase test and C18L based PCR diagnostics (Bera et al., 2011). The pathology of CMLV in different experimental models has been extensively reviewed elsewhere (Duraffour et al., 2011b).
6. Camelpox pathology
7. Host-CMLV interactions
The information about pathology of camelpox is scanty, however in severe form, pox lesions have been observed in the respiratory tract, digestive tract (Bhanuprakash et al., 2010b; Kinne et al., 1998), heart and liver (Pfeffer et al., 1998). The variety in clinical manifestation of the camelpox infection probably indicates the presence of different strains of CMLV with varying degree of viru-
Poxviruses including camelpox utilize a number of strategies to dodge the hostile host immune response, which includes interfering with interferon, complement system and pro-inflammatory cytokines (IL-1, IL-18, Tumor Necrosis Factors) (Duraffour et al., 2011b) (Table 1). Both humoral and cellular immune response play an important role in protecting against CMLV (Alcami et al.,
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Table 1 CMLV proteins and their putative functions/significance. Virus protein/ORF
Function or similarity Immune evasion
Reference
CMLV001 CMLV002 CMLV023 CMLV031 CMLV032 CMLV055 CMLV097 CMLV158 CMLV166 CMLV184 CMLV191 CMLV201 CMLV205 CMLV210 CMLV211 ORF-23L ORF-32L, ORF-55L ORF-176R Viral virulence/Host range CMLV013 CMLV019 CMLV026 CMLV132 CMLV188 CMLV193, CMLV194, CMLV196 CMLV003, CMLV004, CMLV015, CMLV 016, CMLV 017, CMLV028, CMLV180, CMLV199, CMLV200, CMLV202, CMLV 208, CMLV 209, ORF-6L
35-kDa chemokine protein Tumour necrosis factor receptor II crmB Complement binding protein Serine proteinase inhibitors Double-stranded RNA-dependent protein kinase inhibitors Dephosphorylates STAT1 CD47-like protein IL-1/Toll-like receptor inhibitor Interferon-␥ receptor Serine Proteinase Inhibitors Interferon-␣/ binding protein Serine Proteinase Inhibitors Tumour necrosis factor receptor II crmB 35-kDa chemokine protein Complement inhibitor IFN inhibitor Inhibits T-cell growth and development
Najarro et al. (2001) Najarro et al. (2001) Najarro et al. (2001) Bowie et al. (2000) Najarro et al. (2001)
Rabbit fibroma virus- N1R/ectromelia virus p28 host range factor VACV C7L host range N1L virulence A14.5L virulence Myxoma M-T4 virulence protein Inhibits IL-1 Viral host range and prevention of infection-induced apoptosis
Senkevich et al. (1995) Perkus et al. (1990) Kotwal et al. (1990) Betakova et al. (2000) Barry et al. (1997) Afonso et al. (2002) Mossman et al. (1996)
Najarro et al. (2001) Bowie et al. (2000) Bowie et al. (2000) (Moss and Shisler, 2001) Bowie et al. (2000) Moss and Shisler (2001) Bowie et al. (2000) Najarro et al. (2001) Najarro et al. (2001) Kotwal et al. (1990) Smithet al. (1998) Schwarz et al. (1998)
Fig. 1. Camelpox lesions on different body parts of a dromedary camel.
2000). It has been reported that vaccinia virus B18R gene encodes a protein with soluble receptor property which binds to IFN-␣/ with high affinity at the cell surface and protects both infected and non-infected cells from antiviral state (Alcami et al., 2000). CMLV interferes with IL-12 induced IFN-␥ production in mouse splenocytes (Symons et al., 2002). CMLV secretes soluble IFN-␥
receptors which binds and prevents IFN-␥ interaction with the cellular receptors and thus interferes with the its antiviral effect (Alcami and Smith, 1995). CMLV may employ several mechanisms to alter or shut down the host immune response, though these mechanisms have been elucidated in vitro, these may reflect the in vivo conditions in camel (Duraffour et al., 2011b). Most of the
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proteins encoded by poxviruses which interfere with the host immune response target the innate immune system. CMLV encodes for v-GAAP protein, which lies in the Golgi and affects apoptosis, cell adhesion, and migration independently (Carrara et al., 2015; Gubser et al., 2007a). CMLV encodes for a cytoplasmic 57 kDa protein which shows similarity with short mammalian schlafen protein 1 and 2 which attenuates VACV without affecting the virus replication or plaque morphology in vitro. It has been shown that there is increase in the enormity of IL-6, IL-18, CD11c + CD8a+ lymphoid and CD11c + CD11b+ myeloid dendritic cell in the athymic nude mice when challenged intranasal with CMLV (Duraffour et al., 2011a; Gubser et al., 2007b). CMLV has been shown to express a 35kDa chemokine binding protein (vCKBP) which binds CC, but not CXC or C and thus prevents chemokine based immune cells migration to the sites of inflammation and infection in vitro (Alcami et al., 1998).
Orthovac is an inactivated camelpox vaccine which is prepared from strain Al Jouf-78 and it is recommended for subcutaneous injection at six months of age, followed by second vaccination at 4–6 months of primary vaccination and booster dose annually to ensure good protection. An inactivated vaccine derived from CMLV strain T8 has shown its efficacy in protecting camelpox infection in young and adult camels. A good immunity was reported for six to twelve months old camels with camelpox- live attenuated vaccine however same aged camels showed weak immune response with camelpox-inactivated vaccine following three months post-vaccination. Bray and Babiuk have brought attention towards camelpox as next candidature for eradication programme using surveillance, ring-vaccination and quarantine (Bray and Babiuk, 2011).
9. Challenges 8. Immune response and vaccines The immunological immaturity before the birth along with the absence of maternal antibodies makes young animals susceptible to poxvirus infection while the immunity developed after its primary infection is long-lasting (Buller and Palumbo, 1991). It has been shown that camel younger than six months of age have immature immune system towards poxvirus infection. Generalized CMLV infection occurs generally during or immediately after the rainfall and may be associated with a decrease in the immunity of the animal (Gitao, 1997). Both humoral as well as cell mediated immunity plays important role against CMLV infection (Anonymous, 2008). The members of the genus orthopoxvirus share immunity with each other. Moreover, the camels inoculated with smallpox virus showed protection against CMLV infection suggested the cross reactivity of immune molecules (Baxby et al., 1975). In addition, strain specific antibodies and ADCC play an important role in the elimination of the poxvirus infection from the host (Buller and Palumbo, 1991). Interestingly, the negative amplification of CMLV ATIP gene from the blood of infected animal having clear skin lesions suggests virus clearance by specific B-cell response (Chaudhri et al., 2006). However, animals recovered once from CMLV infection remain life-long protected from its reinfection because of the strong memory immune response (Moss, 2007). A live attenuated or inactivated vaccine is available to control camelpox infection. Although the immunity with attenuated vaccine is long lasting, a booster is recommended before 6–9 months. However, annual vaccination is usually practiced in case of inactivated vaccines (Moss, 2007; Wernery and Zachariah, 1999). At present, Ducapox (Dubai CAmelPOX vaccine [UAE]) and “OrthovacR ” (Jordan) are two camelpox vaccines which are available commercially (Wernery and Zachariah, 1999). The Ducapox (modified live CMLV vaccine of strain CaPV298-2 or O.cameli in vero cells) vaccine has also been tried in new world camels where it was able to provide immunity from CMLV challenge without showing adverse effect. Ducapox has also been tested for its safety and potency, and recommended for single subcutaneous injection at six months of age which is sufficient to provide protection for at least one year. It has been shown that an attenuated CMLV strain “Jouf78” provides good immunity against poxvirus (Hafez et al., 1992). In Sudan, an attenuated CMLV strain, Sudan CMLV/115 has been reported safe for young and pregnant animals following challenge by virulent wild-type CMLV in camels (Abdellatif et al., 2015). An attenuated vero cell based camelpox vaccine has been developed with indigenous CMLV strain (Prabhu et al., 2014), however, there are no published reports of vaccination of any kind being practiced for camelpox in India.
It has been pointed out that different strains of camelpox may have difference in their virulence and as such no detail information is available regarding CMLV strains in India (Wernery and Kaaden, 2002). The precipitating factors responsible for the disease occurrence along with molecular epidemology for their proper characterization is required if more than one CMLV strain is responsible for disease occurrence in camel dwelling areas of India. If there is any significant change between virulent and less virulent CMLV strains, its significance in the disease pathogenesis can be an area of exploration. Further, it will be fascinating to explore how different strains of CMLV with varying degree of pathogenicity influence the host immune system such as cellular receptors and cytokines for their own advantage. The virus strain information will be helpful to design vaccine strategy. Similar to other OPVs, exposure to vaccine, or wild-type virus results in the formation of lifelong immunity to the virus (Bhanuprakash et al., 2010b), which modulates with the immune status of the animal (Yousif and Al-Naeem, 2012). The study further emphasized that cutaneous immunity of the camel calf prior and during a vaccine program may be given importance to properly address the cases of reinfection. The incidence of reinfection possess a threat to the healthy camels and their handlers and hence, the importance of routine screening of camels even with prior exposure to CMLV along with duration of virus shedding cannot be overlooked. The basic research involving evaluation of host-CMLV interaction should be investigated to find and develop the new control strategies. Further efforts may be invested to develop a potent, long lasting vaccine with its safety in young and pregnant animals. In addition, proper care to avoid any vaccine failure and eradication campaign of camelpox needs to be implemented in the area of its endemicity. In addition, new strategies for the development of newer vaccine approaches and their adjutants such as Toll-like receptors should be explored. It has been proposed that antagonist of CCR4 can act as adjuvant for tumor vaccine by transiently inhibiting T regulatory cells during vaccination (Bayry et al., 2014; Pere et al., 2012). However, its use in the context of CMLV vaccine requires experimental evidences. It has been shown that ticks analyzed through electron microscope and cell culture were found positive for CMLV (Pfeffer et al., 1996). However, the actual mode of transmission of CMLV (mechanical or biological, i.e. transstadial or transovarial transmission) through tick or involvement of any other vector needs to be explored. It would also be interesting to know the various factors under which these vectors are efficiently capable of transmitting CMLV. The information about spread, pathogenesis and immune response of a viral disease should be supported by robust modeling and prediction programs and corroborated by multidisciplinary approach (Bayry, 2013). A very strict surveillance for any camelpox
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Camelpox: A brief review on its epidemiology, current status and challenges Shyam Singh Dahiya a,∗ , Sachin Kumar b , Sharat Chandra Mehta a , Shirish D. Narnaware a , Raghvendar Singh a , Fateh Chand Tuteja a a b
National Research Center on Camel, Jorbeer, Bikaner, Rajasthan 334001, India Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
a r t i c l e
i n f o
Article history: Received 17 December 2015 Received in revised form 12 February 2016 Accepted 18 February 2016 Available online 20 February 2016 Keywords: Camelpox Zoonosis Outbreak Vaccine Immune evasion
a b s t r a c t Camelpox caused by a Camelpox virus (CMLV) is a very important host specific viral disease of camel. It is highly contagious in nature and causes serious impact on health even mortality of camels and economic losses to the camel owners. It manifests itself either in the local/mild or generalized/severe form. Various outbreaks of different pathogenicity have been reported from camel dwelling areas of the world. CMLV has been characterized in embryonated chicken eggs with the production of characteristic pock lesions and in various cell lines with the capacity to induce giant cells. Being of Poxviridae family, CMLV employs various strategies to impede host immune system and facilitates its own pathogenesis. Both live and attenuated vaccine has been found effective against CMLV infection. The present review gives a comprehensive overview of camelpox disease with respect to its transmission, epidemiology, virion characteristics, viral life cycle, host interaction and its immune modulation. © 2016 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Global scenario . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Virion and genome characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Viral life cycle and viral proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Camelpox pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Host-CMLV interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Immune response and vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
1. Introduction Camelpox is a highly contagious disease of camels with an exception of dromedary camel in Australia and tylopods (llama and related species) in South America (Mosadeghhesari et al., 2014; Pfeffer et al., 1998; Wernery and Kaaden, 2002). The disease can cause high mortality and morbidity in camels leading to greater
∗ Corresponding author. E-mail address: [email protected] (S.S. Dahiya). http://dx.doi.org/10.1016/j.actatropica.2016.02.014 0001-706X/© 2016 Elsevier B.V. All rights reserved.
economic impact in the countries like India and Middle East. The camelpox causes higher mortality in young animals than in adults (Kriz, 1982). The disease can manifest itself in two distinct forms, i.e. milder and localized in old camels or severe and generalized in young camels which may cause heavy mortality (Wernery and Kaaden, 2002). The disease causes a decrease in milk production in lactating animals, weight loss and debilitating condition in all the infected animals (Kinne et al., 1998). Outbreaks have often been attributed to weaning or poor nutrition, which may sometimes result into severe fatality (Bhanuprakash et al., 2010a). Since 1978, the smallpox vaccination has been stopped and the concern has been shown as the human population has become susceptible
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to emerging or re-emerging of any virus from the poxvirus group (VARV, monkeypox, CMLV or taterapox virus) (Gubser and Smith, 2002). Camelpox is important not only to control the economic losses in camel rearing areas (Otterbein et al., 1996) but to deal with it in a logistic and holistic approach to check its spread to other nearby areas also (Bhanuprakash et al., 2010a). Present review gives a comprehensive overview of camelpox disease with respect to its epidemiology, mode of transmission, virion characteristics and its immune modulation. 2. Global scenario In the list of many primordial viral infections known to mankind, poxviruses have its own important place among the most feared viruses of livestock animals and humans (Essbauer et al., 2009). As per the United Nation Food and Agriculture Organization, there are approximately 20 million camels in the world (http://faostat.fao. org). Camelpox was first reported from the Punjab province in India in the year 1909 (Wernery and Kaaden, 2002). Camelpox incidences have been reported from the Middle East, Asia, Africa, Southern Russia and India (Sharawi et al., 2011; Wernery and Kaaden, 2002). OIE has declared camelpox as a reportable disease (Bray and Babiuk, 2011). Sporadic outbreaks of camelpox occur in the camel dwelling areas and their incidences increases seasonally especially, during the rainy season (Anonymous, 2008). From an economic point of view, camelpox is possibly the most important orthopoxviral disease (Azwai et al., 1996). In camel rearing countries, camel provides a mode of transport, milk, meat and wool for both nomadic as well as non-nomadic people (Duraffour et al., 2011b). The presence of camelpox in the camel herd has great significance because of its economical impact over the camel owners (Bett et al., 2009; Pfeffer et al., 1998; Wernery and Kaaden, 2002) in terms of loss of health condition, secondary infections, loss of weight and milk production (Duraffour et al., 2011b). Moreover, camelpox is considered important in camel trade and is viewed carefully in order to avoid its transmission to the adjacent camel harbouring countries (Bhanuprakash et al., 2010a). Further, death of the camel by camelpox deprives camel owners of their milk and makes camel calf undernourished which brings greater threat to dreadful diseases and higher infant mortality (Kriz, 1982). Camelpox has been designated as very contagious and extremely transmissible skin disease of camels. CMLV and variola virus (VARV)—causative agent of smallpox, share genome co-linearity and are also unique in infecting a single host species (Fenner, 1989). Exploring the genomics and biological aspects of CMLV can help us to understand the VARV (Duraffour et al., 2011b) as there is a possibility of smallpox-like disease in some immune-compromised human population following its infection (Baxby, 1975). 3. Epidemiology Housawi, (2007) demonstrated CMLV specific antibody prevalence rate of 0%, 6% and 10% in cattle, sheep and goat respectively, in Saudi Arabia (Housawi, 2007). Based on these results, Duraffour et al., suggested the potential adaptation of camelpox in enzootic areas to hosts other than camel (Duraffour et al., 2011b). CMLV is host specific and isolated reports of some skin lesions in humans have been reported (Bera et al., 2011; Ramyar and Hessami, 1972). The movement of large animal herds facilitates the continued propagation of CMLV. Arthropod vector may also help in propagating the infection and the virus may get transmitted directly from infected camel by skin injuries or through inhalations (Anonymous, 2008; Bera et al., 2011). CMLV has been isolated from the camel tickHyalomma dromedarii harboring camelpox infection (Pfeffer et al., 1996). CMLV may get into the body secretions including milk and
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may survive in the dried scab for as long as four months. CMLV was confirmed in the skin of the camels through PCR and on the CAM of specific-pathogen-free (SPF) embryonated chicken eggs (ECE) even after one year of their previous infection (Yousif and Al-Naeem, 2012). The incubation period of camelpox varies from 3 to 15 days (Anonymous, 2008; Moss, 2007). Depending upon the virus strain, the infection may range from a mild type of skin lesions to moderate and serious systemic infections (Wernery and Kaaden, 2002). Moreover, pregnant animals may abort and the animal dies due to secondary infections and septicaemia (Kriz, 1982). The morbidity rate depends upon the circulation of the virus in the herd (Wernery and Kaaden, 2002). The incidence of camelpox is more in the male camels as compared to the female counterpart while the mortality is higher in the young ones than in the adults (Kriz, 1982). The disease is often associated with poor nutrition (Bhanuprakash et al., 2010a). Besides other factors, the virus gets transmitted from infected to healthy camel through shared animal husbandry practices.
4. Virion and genome characteristics The etiological agent of camelpox disease in camels is an epitheliotropic DNA virus (Salem et al., 2008). It is a member of the genus Orthopoxvirus (OPV) under subfamily Chordopoxvirinae and the family Poxviridae (Essbauer et al., 2009). The brick shaped virion is 265–295 nm in size and surrounded by an outer membrane studded with irregularly arranged tubular proteins (Moss, 2007). CMLV replicates in the cytoplasm and carries a large number of viral encoded enzymes, associated within the virion. CMLV is ether resistant and chloroform sensitive (Moss, 2007). CMLV remained unaffected between a pH range of 3–8.5 for one hour and resists heat at 56 ◦ C for one hour; however, its infectivity com◦ pletely disappeared at 70 C after 30 min (Falluji et al., 1979). The genome of CMLV is composed of a single linear double-stranded DNA molecule of 205,719 bp and contains 211 putative genes (Afonso et al., 2002). The genome of CMLV consists of a central region bound by identical inverted terminal repeats of approximately 7 kbp. Although the genome of CMLV shares close structural and functional similarities with other OPVs, it contains unique region of about 3kbp encoding for three ORFs (CMLV185, CMLV186, CMLV187) which are absent in other OPVs (Afonso et al., 2002). The genes in the middle of the orthopoxviruses genome are conserved while towards either terminal are variable, which encodes proteins involved with host tropism, virulence or immunomodulation (Gubser and Smith, 2002). Based on nucleotide sequence analysis, the CMLV is most closely related to VARV. The CMLV-CMS ITR just like variola virus encodes proteins within 650 bp of its terminus (Massung et al., 1994; Shchelkunov et al., 1995, 2000). At nucleotide level, CMLV and VAR shares 96.6–98.6% identity. The DNA distance matrix also showed lower genetic distance between CMLV and VAR than between CMLV and vaccinia virus. The percentage amino acid identity of CMLV with other poxviruses showed that CMLV is more closely related to VAR than any other viruses. The camelpox genome is composed of 66.9% A + T and has a distinctive Hind III restriction map (Gubser and Smith, 2002). Till date about 45 serotypes have been reported for CMLV and three serotypes (CMLV1, CMLV2 and CMLV-Hyd 06) are more prevalent in Indian subcontinent while serotypes 19 and 16 are prevalent in the Middle East and Africa respectively. These strains have different physicochemical properties and manifest themselves differently in various cells and in embryonated chicken eggs (Duraffour et al., 2011b).
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5. Viral life cycle and viral proteins Unlike other DNA viruses, poxviruses rely mostly on the virusencoded proteins for their replication in the cytoplasm (Moss, 2007, 2012). Most of the information regarding the poxvirus replication has been deduced utilizing vaccinia virus as a model in mammalian cells (Buller and Palumbo, 1991). The mature virion enters either by fusing with the host cell by interacting with glycosaminoglycans at the cell surface or with the endosomal membrane (White et al., 2008). Although poxviruses have not been reported for any single receptor mediated adsorption to the cell (Buller and Palumbo, 1991), 11–12 proteins are enlisted for its post-attachment entry (Moss, 2012). CMLV fuses with the host cell membrane and releases as an extracellular enveloped virion (EEV/EV) (Smith et al., 2002; Ward and Moss, 2001). The uncoating of the poxvirus starts with the loss of virion proteins and lipid (Dales, 1965) followed by loss of its core membrane (Holowczak, 1972; Sarov and Joklik, 1972). Deterrence of uncoating has been reported by the inhibition of transcription or translation indicating that either the virus induced or its encoded proteins are required for its uncoating (Joklik, 1964), About 50% of the transcripts get capped and polyadenylated once the core (containing DNA, viral encoded enzymes and early transcriptional factor) of the virus reaches the cytoplasm (Kates and Beeson, 1970; Kates and McAuslan, 1967; Moss, 1990). Virus encoded DNA polymerase, thymidine kinase, thymidylate kinase ensure availability of DNA for its replication. Vaccinia virus encoded proteins like virus growth factor and complement-binding protein deal with its spread and blocks classical complement pathway by binding with C4b, respectively (Buller et al., 1988a, 1988b; Kotwal et al., 1990; Stroobant et al., 1985). Poxvirus replication occurs in the cytoplasm at specific site known as viroplasm (Buller and Palumbo, 1991). The high level of recombination in the poxvirus infected cells promoted evolution and gain of beneficial functions which facilitate the multiplication and its transmission without causing premature mortality of the host (Buller and Palumbo, 1991). DNA replication is followed by intermediate and late classes of mRNA and protein synthesis (Moss, 2012). Virus packaging and its release as a mature virion (MV) with single external membrane or as a wrapped virion (WV) with triple membrane takes place after the expression its late genes (Cyrklaff et al., 2005; Heuser, 2005; Hollinshead et al., 1999). MVs are assumed to facilitate spread between the host while EVs are believed to mediate spread within the host (Moss, 2012). Depending upon the poxvirus and infected cell, the virion may exit through microvilli (Ichihashi et al., 1971) or Golgi apparatus (Dales and Pogo, 1981). Poxvirus can acquire its envelope from a vacuole (Purcell et al., 1972) and released from cell through non-membrane-bound vacuoles (Sutton and Burnett, 1969) or by A-type inclusion body (Ichihashi and Matsumoto, 1966; Ichihashi et al., 1971). CMLV encodes 211 putative genes encoding various proteins of length 53–1869 amino acids long. CMLV encodes for similar proteins as those present in other orthopoxvirus viz. proteins associated with virion core, intracellular mature virus (IMV), enzymes associated with protein modification, DNA packaging and release of Extracellular enveloped virion (EEV) (Afonso et al., 2002). Some of the viral proteins having a pivotal role in immune evasion, determining host range and virulence are summarized in Table 1.
lence. Following 1–3 days of fever and lymph nodes enlargement, skin lesions appear starting from erythematous macules, papules, vesicles and finally into a pustules (Ayelet et al., 2013). The lesions appear first on the head and then progresses to the rest of the body parts (Fig. 1). In systemic form, the disease prognosis is usually grave, the signs include anorexia or diarrhoea and the lesion may appear on the mucous membrane of mouth respiratory and digestive tract. Histopathologically, the lung lesions are consolidated with expanded alveoli and a small number of diphtheroid lesions in the tracheal mucosa (Kinne et al., 1998). In pulmonary lesions, the initial lung lesions have been shown to contain hydropic degeneration and infilteration of affected areas by macrophages with foci of proliferative alveolitis and bronchiolitis. Histopathological examination of lung shows foci of proliferated bronchial epithelium, necrosis and fibrosis (Kinne et al., 1998). Histopathology of the skin lesions from free-ranging camels suggestive of camelpox have been reported to display significant acanthosis with degeneration of acanthocytes. In addition, hyperkeratosis and dermal layer infiltrated with inflammatory cells mainly neutrophils along with dermal fibroplasias has also been reported (Motalab and Ahmed, 2014). Chorioallantoic Membrane (CAM) route has been employed by various researchers to isolate CMLV in 11–13 day old ECE. The grayish white pock lesions can be observed in eggs infected with CMLV five days post inoculation (Al-Zi’abi et al., 2007; Davies et al., 1975; Duraffour et al., 2011b; Falluji et al., 1979; Sheikh Ali et al., 2009; Yousif and Al-Naeem, 2012). Numerous cell lines of different origin have been utilized successfully to culture CMLV. In general, cell lines derived from camel, monkey, chicken, lamb, calf, horse, human, hamster, mouse and dog support one or another strain of CMLV (Duraffour et al., 2011b). Usually, the cells infected with CMLV show characteristic CPE in the form of rounding and ballooning of cells, micro-plaque formation, cytoplasmic elongation, and syncytia formation (Al-Zi’abi et al., 2007; Ayelet et al., 2013; Bhanuprakash et al., 2010a; Davies et al., 1975; Duraffour et al., 2011b; Falluji et al., 1979; Mosadeghhesari et al., 2014; Sheikh Ali et al., 2009). The exploration of other species as an alternative host for CMLV has not been encouraging in rabbit, mice, cattle, sheep, goat, guinea pig, rats, hamsters and chickens (Bhanuprakash et al., 2010a; Davies et al., 1975; Falluji et al., 1979; Ramyar and Hessami, 1972). CMLV infection of athymic nude mice via the intranasal route has been reported to result in failure to gain body weight while its intracutaneous infection resulted in the disseminated lesions. It is interesting to note that cells originated from human have been utilized to carry out CMLV based studies (Duraffour et al., 2007). Davies et al. have reported the development of ulcers on the lips and mouth of the people consuming milk from the camelpox affected camels in Northern Kenya (Davies et al., 1975). Although CMLV could not be isolated from any of the human subjects, three cases have been reported from India which were confirmed by counter immunoelectrophoresis (CIE); serum neutralization test (SNT); plaque-reduction neutralization test (PRNT), indirect immunoperoxidase test and C18L based PCR diagnostics (Bera et al., 2011). The pathology of CMLV in different experimental models has been extensively reviewed elsewhere (Duraffour et al., 2011b).
6. Camelpox pathology
7. Host-CMLV interactions
The information about pathology of camelpox is scanty, however in severe form, pox lesions have been observed in the respiratory tract, digestive tract (Bhanuprakash et al., 2010b; Kinne et al., 1998), heart and liver (Pfeffer et al., 1998). The variety in clinical manifestation of the camelpox infection probably indicates the presence of different strains of CMLV with varying degree of viru-
Poxviruses including camelpox utilize a number of strategies to dodge the hostile host immune response, which includes interfering with interferon, complement system and pro-inflammatory cytokines (IL-1, IL-18, Tumor Necrosis Factors) (Duraffour et al., 2011b) (Table 1). Both humoral and cellular immune response play an important role in protecting against CMLV (Alcami et al.,
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Table 1 CMLV proteins and their putative functions/significance. Virus protein/ORF
Function or similarity Immune evasion
Reference
CMLV001 CMLV002 CMLV023 CMLV031 CMLV032 CMLV055 CMLV097 CMLV158 CMLV166 CMLV184 CMLV191 CMLV201 CMLV205 CMLV210 CMLV211 ORF-23L ORF-32L, ORF-55L ORF-176R Viral virulence/Host range CMLV013 CMLV019 CMLV026 CMLV132 CMLV188 CMLV193, CMLV194, CMLV196 CMLV003, CMLV004, CMLV015, CMLV 016, CMLV 017, CMLV028, CMLV180, CMLV199, CMLV200, CMLV202, CMLV 208, CMLV 209, ORF-6L
35-kDa chemokine protein Tumour necrosis factor receptor II crmB Complement binding protein Serine proteinase inhibitors Double-stranded RNA-dependent protein kinase inhibitors Dephosphorylates STAT1 CD47-like protein IL-1/Toll-like receptor inhibitor Interferon-␥ receptor Serine Proteinase Inhibitors Interferon-␣/ binding protein Serine Proteinase Inhibitors Tumour necrosis factor receptor II crmB 35-kDa chemokine protein Complement inhibitor IFN inhibitor Inhibits T-cell growth and development
Najarro et al. (2001) Najarro et al. (2001) Najarro et al. (2001) Bowie et al. (2000) Najarro et al. (2001)
Rabbit fibroma virus- N1R/ectromelia virus p28 host range factor VACV C7L host range N1L virulence A14.5L virulence Myxoma M-T4 virulence protein Inhibits IL-1 Viral host range and prevention of infection-induced apoptosis
Senkevich et al. (1995) Perkus et al. (1990) Kotwal et al. (1990) Betakova et al. (2000) Barry et al. (1997) Afonso et al. (2002) Mossman et al. (1996)
Najarro et al. (2001) Bowie et al. (2000) Bowie et al. (2000) (Moss and Shisler, 2001) Bowie et al. (2000) Moss and Shisler (2001) Bowie et al. (2000) Najarro et al. (2001) Najarro et al. (2001) Kotwal et al. (1990) Smithet al. (1998) Schwarz et al. (1998)
Fig. 1. Camelpox lesions on different body parts of a dromedary camel.
2000). It has been reported that vaccinia virus B18R gene encodes a protein with soluble receptor property which binds to IFN-␣/ with high affinity at the cell surface and protects both infected and non-infected cells from antiviral state (Alcami et al., 2000). CMLV interferes with IL-12 induced IFN-␥ production in mouse splenocytes (Symons et al., 2002). CMLV secretes soluble IFN-␥
receptors which binds and prevents IFN-␥ interaction with the cellular receptors and thus interferes with the its antiviral effect (Alcami and Smith, 1995). CMLV may employ several mechanisms to alter or shut down the host immune response, though these mechanisms have been elucidated in vitro, these may reflect the in vivo conditions in camel (Duraffour et al., 2011b). Most of the
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proteins encoded by poxviruses which interfere with the host immune response target the innate immune system. CMLV encodes for v-GAAP protein, which lies in the Golgi and affects apoptosis, cell adhesion, and migration independently (Carrara et al., 2015; Gubser et al., 2007a). CMLV encodes for a cytoplasmic 57 kDa protein which shows similarity with short mammalian schlafen protein 1 and 2 which attenuates VACV without affecting the virus replication or plaque morphology in vitro. It has been shown that there is increase in the enormity of IL-6, IL-18, CD11c + CD8a+ lymphoid and CD11c + CD11b+ myeloid dendritic cell in the athymic nude mice when challenged intranasal with CMLV (Duraffour et al., 2011a; Gubser et al., 2007b). CMLV has been shown to express a 35kDa chemokine binding protein (vCKBP) which binds CC, but not CXC or C and thus prevents chemokine based immune cells migration to the sites of inflammation and infection in vitro (Alcami et al., 1998).
Orthovac is an inactivated camelpox vaccine which is prepared from strain Al Jouf-78 and it is recommended for subcutaneous injection at six months of age, followed by second vaccination at 4–6 months of primary vaccination and booster dose annually to ensure good protection. An inactivated vaccine derived from CMLV strain T8 has shown its efficacy in protecting camelpox infection in young and adult camels. A good immunity was reported for six to twelve months old camels with camelpox- live attenuated vaccine however same aged camels showed weak immune response with camelpox-inactivated vaccine following three months post-vaccination. Bray and Babiuk have brought attention towards camelpox as next candidature for eradication programme using surveillance, ring-vaccination and quarantine (Bray and Babiuk, 2011).
9. Challenges 8. Immune response and vaccines The immunological immaturity before the birth along with the absence of maternal antibodies makes young animals susceptible to poxvirus infection while the immunity developed after its primary infection is long-lasting (Buller and Palumbo, 1991). It has been shown that camel younger than six months of age have immature immune system towards poxvirus infection. Generalized CMLV infection occurs generally during or immediately after the rainfall and may be associated with a decrease in the immunity of the animal (Gitao, 1997). Both humoral as well as cell mediated immunity plays important role against CMLV infection (Anonymous, 2008). The members of the genus orthopoxvirus share immunity with each other. Moreover, the camels inoculated with smallpox virus showed protection against CMLV infection suggested the cross reactivity of immune molecules (Baxby et al., 1975). In addition, strain specific antibodies and ADCC play an important role in the elimination of the poxvirus infection from the host (Buller and Palumbo, 1991). Interestingly, the negative amplification of CMLV ATIP gene from the blood of infected animal having clear skin lesions suggests virus clearance by specific B-cell response (Chaudhri et al., 2006). However, animals recovered once from CMLV infection remain life-long protected from its reinfection because of the strong memory immune response (Moss, 2007). A live attenuated or inactivated vaccine is available to control camelpox infection. Although the immunity with attenuated vaccine is long lasting, a booster is recommended before 6–9 months. However, annual vaccination is usually practiced in case of inactivated vaccines (Moss, 2007; Wernery and Zachariah, 1999). At present, Ducapox (Dubai CAmelPOX vaccine [UAE]) and “OrthovacR ” (Jordan) are two camelpox vaccines which are available commercially (Wernery and Zachariah, 1999). The Ducapox (modified live CMLV vaccine of strain CaPV298-2 or O.cameli in vero cells) vaccine has also been tried in new world camels where it was able to provide immunity from CMLV challenge without showing adverse effect. Ducapox has also been tested for its safety and potency, and recommended for single subcutaneous injection at six months of age which is sufficient to provide protection for at least one year. It has been shown that an attenuated CMLV strain “Jouf78” provides good immunity against poxvirus (Hafez et al., 1992). In Sudan, an attenuated CMLV strain, Sudan CMLV/115 has been reported safe for young and pregnant animals following challenge by virulent wild-type CMLV in camels (Abdellatif et al., 2015). An attenuated vero cell based camelpox vaccine has been developed with indigenous CMLV strain (Prabhu et al., 2014), however, there are no published reports of vaccination of any kind being practiced for camelpox in India.
It has been pointed out that different strains of camelpox may have difference in their virulence and as such no detail information is available regarding CMLV strains in India (Wernery and Kaaden, 2002). The precipitating factors responsible for the disease occurrence along with molecular epidemology for their proper characterization is required if more than one CMLV strain is responsible for disease occurrence in camel dwelling areas of India. If there is any significant change between virulent and less virulent CMLV strains, its significance in the disease pathogenesis can be an area of exploration. Further, it will be fascinating to explore how different strains of CMLV with varying degree of pathogenicity influence the host immune system such as cellular receptors and cytokines for their own advantage. The virus strain information will be helpful to design vaccine strategy. Similar to other OPVs, exposure to vaccine, or wild-type virus results in the formation of lifelong immunity to the virus (Bhanuprakash et al., 2010b), which modulates with the immune status of the animal (Yousif and Al-Naeem, 2012). The study further emphasized that cutaneous immunity of the camel calf prior and during a vaccine program may be given importance to properly address the cases of reinfection. The incidence of reinfection possess a threat to the healthy camels and their handlers and hence, the importance of routine screening of camels even with prior exposure to CMLV along with duration of virus shedding cannot be overlooked. The basic research involving evaluation of host-CMLV interaction should be investigated to find and develop the new control strategies. Further efforts may be invested to develop a potent, long lasting vaccine with its safety in young and pregnant animals. In addition, proper care to avoid any vaccine failure and eradication campaign of camelpox needs to be implemented in the area of its endemicity. In addition, new strategies for the development of newer vaccine approaches and their adjutants such as Toll-like receptors should be explored. It has been proposed that antagonist of CCR4 can act as adjuvant for tumor vaccine by transiently inhibiting T regulatory cells during vaccination (Bayry et al., 2014; Pere et al., 2012). However, its use in the context of CMLV vaccine requires experimental evidences. It has been shown that ticks analyzed through electron microscope and cell culture were found positive for CMLV (Pfeffer et al., 1996). However, the actual mode of transmission of CMLV (mechanical or biological, i.e. transstadial or transovarial transmission) through tick or involvement of any other vector needs to be explored. It would also be interesting to know the various factors under which these vectors are efficiently capable of transmitting CMLV. The information about spread, pathogenesis and immune response of a viral disease should be supported by robust modeling and prediction programs and corroborated by multidisciplinary approach (Bayry, 2013). A very strict surveillance for any camelpox
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