- Email: [email protected]
Zika and microcephaly: causation, correlation, or coincidence?
Accepted Manuscript Zika and microcephaly: causation, correlation, or coincidence? Jason A. Tetro PII:
S1286-4579(16)00008-3
DOI:
10.1016/j.micinf.2015.12.010
Reference:
MICINF 4365
To appear in:
Microbes and Infection
Received Date: 20 December 2015
Please cite this article as: J.A. Tetro, Zika and microcephaly: causation, correlation, or coincidence?, Microbes and Infection (2016), doi: 10.1016/j.micinf.2015.12.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI PT
Commentary
AC C
EP
TE D
M AN U
Author Jason A. Tetro, B.Sc.
SC
Zika and microcephaly: causation, correlation, or coincidence?
130 Rosedale Valley Rd. Suite 103 Toronto, Ontario, Canada M4W 1P9 [email protected]
ACCEPTED MANUSCRIPT
In November, the Brazilian Ministry of Health released a report declaring a dramatic rise in the number of microcephaly cases, particularly in the Pernambuco state [1]. Although a definitive cause was not declared, the Ministry suggested an association with Zika virus infection. This
RI PT
was a bold move by the government and raised the question as to whether Zika caused this
condition, correlated with it, or had no involvement at all other than coincidence. At the time, no concrete answers were available casting a shadow on the statement and the government. Yet,
SC
based on previous studies on the virus and the mechanism behind microcephaly, the claim might
M AN U
not be entirely irrational.
Zika virus is a member of the Flaviviridae family, which includes Dengue and West Nile Virus. Vertical transmission of Dengue [2] has been demonstrated resulting in infection and a risk for death. In contrast, perinatal transmission of WNV [3] has not been observed as only cord blood antibodies have been detected. In Brazil, Zika viral RNA has been detected both in the mothers
TE D
and amniotic fluid samples from the fetuses. Thus, Zika virus may have the potential to infect the fetus and potentially cause neurodevelopmental dysfunction including microcephaly.
EP
The pathological properties of Zika were first described in 1952, when Dick et al. [4] demonstrated viral tropism to the brain in intraperitoneally infected mice and an increase in viral
AC C
titres over several days. This research suggested the virus could cross the blood brain barrier. The research findings were complemented in 1972 by Bell and colleagues [5] who observed the progression of disease in directly infected mouse brains. Based on their observations, the virus infected both neurons and glia, producing a variety of intracytoplasmic inclusions, which they termed, “virus factories.” These factories originated from the endoplasmic reticulum and associated with other organelles including the nucleus and the mitochondria.
ACCEPTED MANUSCRIPT
Those microscopic observations describe what we now know as autophagy. As discussed by Travassos and Carneiro in this issue, this cellular process is designed to ensure cell homeostasis through entrapment and eventual degradation of unwanted cellular material. This mechanism is
RI PT
also used to combat viral infection although the efficiency is varied as a result of viral regulatory mechanisms [6]. In the case of flavivirus infection [7], for example, interactions between the virus and the Endoplasmic Reticulum induce autophagy. Yet these viruses prevent completion
M AN U
factories” to maximize viral replication and amplification.
SC
of the autophagy process, flux [8], providing a perfect environment for the creation of “viral
Although autophagy has not been described in Zika-infected neural cells, experimentallyinfected skin fibroblasts [9] have shown autophagy does occur and the virus hijacks this biological process for replication. This provides some evidence to support the involvement of Zika virus in other cell lineages, including as seen by Bell et al [5], neural cells. This also offers
TE D
a potential path to determining whether the virus is directly, indirectly, or not involved in the development of microcephaly.
EP
One of the causes of microcephaly involves abnormal function of centrosomes [10]. Although normally associated with mitosis, these organelles are also involved in other cellular processes
AC C
including migration, polarity and proper trafficking of vesicles. In reference to microcephaly [11], amplification of centrosome number has been revealed to be one of the inducers of this condition. Certain proteins have a dual role in autophagy as well as centrosome stability. One particular example is ultraviolent (UV) irradiation resistance-associated gene (UVRAG). It is involved in initiation and maturation of autophagosomes [12] as well as centrosome and chromosome stability [13]. Another is Beclin-1, which plays an integral role in autophagy and is known to contribute to chromosomal stability in cancer cells [14]. In the context of neural brain
ACCEPTED MANUSCRIPT
development, an increase in centrosomes in mice [11] results in a delay in mitosis, an increase in apoptosis, improper neural stem cell orientation, premature neuronal differentiation, and a
the reduced brain size indicative of microcephaly.
RI PT
decrease in progenitor cells. The overall effect reduces the formation of brain matter leading to
Although the mechanisms of Zika virus pathogenesis appear to fall in line with the requirements
SC
for centrosome abnormalities, there is as of yet no evidence to prove culpability. Future studies need to be performed in order to establish and solidify this link. In particular, vertical
M AN U
transmission of Zika virus needs to be concretely demonstrated as well as any direct or indirect effects of infection on neural development. Furthermore, studies should explore other aberrations in fetal development apart from microcephaly. This is an important consideration since the roles of proper centrosome segregation, chromosomal stability, and autophagy are not restricted to
References:
TE D
neural development suggesting other possible sequelae may be possible.
[1] Agência Saúde. MICROCEFALIA Ministério da Saúde divulga boletim epidemiológico.
EP
2015; http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/20805ministerio-da-saude-divulga-boletim-epidemiologico.
AC C
[2] Chye JK, Lim CT, Ng KB, Lim JM, George R, Lam SK. Vertical transmission of dengue. Clin Infect Dis 1997;25:1374-7. [3] Paisley JE, Hinckley AF, O'Leary DR, Kramer WC, Lanciotti RS, Campbell GL, et al. West Nile virus infection among pregnant women in a northern Colorado community, 2003 to 2004. Pediatrics 2006;117:814-20.
ACCEPTED MANUSCRIPT
[4] Dick GW. Zika virus. II. Pathogenicity and physical properties. Trans R Soc Trop Med Hyg 1952;46:521-34. [5] Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice.
RI PT
Arch Gesamte Virusforsch 1971;35:183-93.
[6] Dreux M, Chisari FV. Viruses and the autophagy machinery. Cell Cycle 2010;9:1295-307. [7] Blazquez AB, Escribano-Romero E, Merino-Ramos T, Saiz JC, Martin-Acebes MA. Stress
SC
responses in flavivirus-infected cells: activation of unfolded protein response and autophagy. Front Microbiol 2014;5:266.
M AN U
[8] Jheng JR, Ho JY, Horng JT. ER stress, autophagy, and RNA viruses. Front Microbiol 2014;5:388.
[9] Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, et al. Biology of Zika Virus Infection in Human Skin Cells. J Virol 2015;89:8880-96.
2009;25:501-10.
TE D
[10] Thornton GK, Woods CG. Primary microcephaly: do all roads lead to Rome? Trends Genet
[11] Marthiens V, Rujano MA, Pennetier C, Tessier S, Paul-Gilloteaux P, Basto R. Centrosome
EP
amplification causes microcephaly. Nat Cell Biol 2013;15:731-40. [12] Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, et al. Beclin1-binding UVRAG
AC C
targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 2008;10:776-87. [13] Zhao Z, Oh S, Li D, Ni D, Pirooz SD, Lee JH, et al. A dual role for UVRAG in maintaining chromosomal stability independent of autophagy. Dev Cell 2012;22:1001-16. [14] Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007;21:1367-81.
S1286-4579(16)00008-3
DOI:
10.1016/j.micinf.2015.12.010
Reference:
MICINF 4365
To appear in:
Microbes and Infection
Received Date: 20 December 2015
Please cite this article as: J.A. Tetro, Zika and microcephaly: causation, correlation, or coincidence?, Microbes and Infection (2016), doi: 10.1016/j.micinf.2015.12.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI PT
Commentary
AC C
EP
TE D
M AN U
Author Jason A. Tetro, B.Sc.
SC
Zika and microcephaly: causation, correlation, or coincidence?
130 Rosedale Valley Rd. Suite 103 Toronto, Ontario, Canada M4W 1P9 [email protected]
ACCEPTED MANUSCRIPT
In November, the Brazilian Ministry of Health released a report declaring a dramatic rise in the number of microcephaly cases, particularly in the Pernambuco state [1]. Although a definitive cause was not declared, the Ministry suggested an association with Zika virus infection. This
RI PT
was a bold move by the government and raised the question as to whether Zika caused this
condition, correlated with it, or had no involvement at all other than coincidence. At the time, no concrete answers were available casting a shadow on the statement and the government. Yet,
SC
based on previous studies on the virus and the mechanism behind microcephaly, the claim might
M AN U
not be entirely irrational.
Zika virus is a member of the Flaviviridae family, which includes Dengue and West Nile Virus. Vertical transmission of Dengue [2] has been demonstrated resulting in infection and a risk for death. In contrast, perinatal transmission of WNV [3] has not been observed as only cord blood antibodies have been detected. In Brazil, Zika viral RNA has been detected both in the mothers
TE D
and amniotic fluid samples from the fetuses. Thus, Zika virus may have the potential to infect the fetus and potentially cause neurodevelopmental dysfunction including microcephaly.
EP
The pathological properties of Zika were first described in 1952, when Dick et al. [4] demonstrated viral tropism to the brain in intraperitoneally infected mice and an increase in viral
AC C
titres over several days. This research suggested the virus could cross the blood brain barrier. The research findings were complemented in 1972 by Bell and colleagues [5] who observed the progression of disease in directly infected mouse brains. Based on their observations, the virus infected both neurons and glia, producing a variety of intracytoplasmic inclusions, which they termed, “virus factories.” These factories originated from the endoplasmic reticulum and associated with other organelles including the nucleus and the mitochondria.
ACCEPTED MANUSCRIPT
Those microscopic observations describe what we now know as autophagy. As discussed by Travassos and Carneiro in this issue, this cellular process is designed to ensure cell homeostasis through entrapment and eventual degradation of unwanted cellular material. This mechanism is
RI PT
also used to combat viral infection although the efficiency is varied as a result of viral regulatory mechanisms [6]. In the case of flavivirus infection [7], for example, interactions between the virus and the Endoplasmic Reticulum induce autophagy. Yet these viruses prevent completion
M AN U
factories” to maximize viral replication and amplification.
SC
of the autophagy process, flux [8], providing a perfect environment for the creation of “viral
Although autophagy has not been described in Zika-infected neural cells, experimentallyinfected skin fibroblasts [9] have shown autophagy does occur and the virus hijacks this biological process for replication. This provides some evidence to support the involvement of Zika virus in other cell lineages, including as seen by Bell et al [5], neural cells. This also offers
TE D
a potential path to determining whether the virus is directly, indirectly, or not involved in the development of microcephaly.
EP
One of the causes of microcephaly involves abnormal function of centrosomes [10]. Although normally associated with mitosis, these organelles are also involved in other cellular processes
AC C
including migration, polarity and proper trafficking of vesicles. In reference to microcephaly [11], amplification of centrosome number has been revealed to be one of the inducers of this condition. Certain proteins have a dual role in autophagy as well as centrosome stability. One particular example is ultraviolent (UV) irradiation resistance-associated gene (UVRAG). It is involved in initiation and maturation of autophagosomes [12] as well as centrosome and chromosome stability [13]. Another is Beclin-1, which plays an integral role in autophagy and is known to contribute to chromosomal stability in cancer cells [14]. In the context of neural brain
ACCEPTED MANUSCRIPT
development, an increase in centrosomes in mice [11] results in a delay in mitosis, an increase in apoptosis, improper neural stem cell orientation, premature neuronal differentiation, and a
the reduced brain size indicative of microcephaly.
RI PT
decrease in progenitor cells. The overall effect reduces the formation of brain matter leading to
Although the mechanisms of Zika virus pathogenesis appear to fall in line with the requirements
SC
for centrosome abnormalities, there is as of yet no evidence to prove culpability. Future studies need to be performed in order to establish and solidify this link. In particular, vertical
M AN U
transmission of Zika virus needs to be concretely demonstrated as well as any direct or indirect effects of infection on neural development. Furthermore, studies should explore other aberrations in fetal development apart from microcephaly. This is an important consideration since the roles of proper centrosome segregation, chromosomal stability, and autophagy are not restricted to
References:
TE D
neural development suggesting other possible sequelae may be possible.
[1] Agência Saúde. MICROCEFALIA Ministério da Saúde divulga boletim epidemiológico.
EP
2015; http://portalsaude.saude.gov.br/index.php/cidadao/principal/agencia-saude/20805ministerio-da-saude-divulga-boletim-epidemiologico.
AC C
[2] Chye JK, Lim CT, Ng KB, Lim JM, George R, Lam SK. Vertical transmission of dengue. Clin Infect Dis 1997;25:1374-7. [3] Paisley JE, Hinckley AF, O'Leary DR, Kramer WC, Lanciotti RS, Campbell GL, et al. West Nile virus infection among pregnant women in a northern Colorado community, 2003 to 2004. Pediatrics 2006;117:814-20.
ACCEPTED MANUSCRIPT
[4] Dick GW. Zika virus. II. Pathogenicity and physical properties. Trans R Soc Trop Med Hyg 1952;46:521-34. [5] Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice.
RI PT
Arch Gesamte Virusforsch 1971;35:183-93.
[6] Dreux M, Chisari FV. Viruses and the autophagy machinery. Cell Cycle 2010;9:1295-307. [7] Blazquez AB, Escribano-Romero E, Merino-Ramos T, Saiz JC, Martin-Acebes MA. Stress
SC
responses in flavivirus-infected cells: activation of unfolded protein response and autophagy. Front Microbiol 2014;5:266.
M AN U
[8] Jheng JR, Ho JY, Horng JT. ER stress, autophagy, and RNA viruses. Front Microbiol 2014;5:388.
[9] Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, et al. Biology of Zika Virus Infection in Human Skin Cells. J Virol 2015;89:8880-96.
2009;25:501-10.
TE D
[10] Thornton GK, Woods CG. Primary microcephaly: do all roads lead to Rome? Trends Genet
[11] Marthiens V, Rujano MA, Pennetier C, Tessier S, Paul-Gilloteaux P, Basto R. Centrosome
EP
amplification causes microcephaly. Nat Cell Biol 2013;15:731-40. [12] Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, et al. Beclin1-binding UVRAG
AC C
targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 2008;10:776-87. [13] Zhao Z, Oh S, Li D, Ni D, Pirooz SD, Lee JH, et al. A dual role for UVRAG in maintaining chromosomal stability independent of autophagy. Dev Cell 2012;22:1001-16. [14] Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007;21:1367-81.