- Email: [email protected]
Is Usutu virus ready for prime time?
Accepted Manuscript Is Usutu Virus Ready For Prime Time? Jason A. Tetro, B.Sc. PII:
S1286-4579(17)30086-2
DOI:
10.1016/j.micinf.2017.05.004
Reference:
MICINF 4474
To appear in:
Microbes and Infection
Received Date: 22 May 2017 Accepted Date: 30 May 2017
Please cite this article as: J.A. Tetro, Is Usutu Virus Ready For Prime Time?, Microbes and Infection (2017), doi: 10.1016/j.micinf.2017.05.004. 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
Commentary
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Is Usutu Virus Ready For Prime Time?
SC
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M AN U
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Author
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Jason A. Tetro, B.Sc.
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EP
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AC C
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TE D
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College of Biological Sciences, University of Guelph Guelph, Ontario, N1G 2W1 [email protected]
ACCEPTED MANUSCRIPT
Mosquito-borne viruses have gained significant attention recently thanks in part to the
21
emergence of the Zika virus (ZIKV) in the Americas. Unfortunately, these infectious agents for
22
the most part have been neglected in the larger public health and research communities. This has
23
resulted in a gap of knowledge on various aspects of infection including pathogenesis, tissue
24
tropism, and the impact of co-morbidities. The research surge in research on ZIKV has provided
25
us with a better understanding of the mechanisms behind the development of symptoms such as
26
microcephaly, Guillain-Barré syndrome, and meningoencephalitis. Yet, we can neither deny the
27
extent by which public health researchers and officials were taken off guard nor ignore the need
28
to continue catching up to other viruses as they continue to spread.
29
Dealing with neglected diseases is difficult at best as limited resources purport a need for
30
research and surveillance prioritization. Though some fifteen-hundred pathogens exist
31
worldwide, there are not enough funds to study them all in a translational manner. This leads to
32
gaps in knowledge and ultimately, treatment options. Additionally, surveillance provides
33
perspective on the relative risk certain pathogens portend. Yet these activities may offer little to
34
no valuable return.
35
One such example of an emerging neglected disease caught in this conundrum is Usutu virus
36
(USUV). Although the name still is relatively obscure in public health sectors, its history and
37
biology have been known for some time (1). This member of the Flavivirus family, first
38
discovered in 1959 in South Africa, circulates in several mosquito species, and infects both avian
39
and mammalian hosts. The virus has since spread into Europe (2) and is considered endemic in
40
certain Central and Eastern regions of the continent. Yet the threat to human health in these areas
41
has not been fully elucidated.
AC C
EP
TE D
M AN U
SC
RI PT
20
ACCEPTED MANUSCRIPT
The first cases of USUV human infection in Europe were documented in 2009 when virus was
43
isolated from blood (3) and viral RNA was detected in cerebrospinal fluid (CSF) (4) of
44
immunocompromised patients in Italy. The find led researchers in these cases to suggest USUV
45
may have evolved such that it could infect humans. However, due to the frail immunity of the
46
patients, the potential for outbreaks in immunocompetent populations was considered to be
47
unlikely. Supporting this assessment was a study by Gaibani et al (5), who performed a survey of
48
359 Italian blood donors. Only four revealed USUV-specific antibodies with no evidence of
49
symptoms.
50
The only case in which an immunocompetent individual presented with neurological defects with
51
USUV infection occurred in Croatia in 2013 in Croatia (6). The twenty-nine year old patient was
52
one of three cases discovered during this time but was the only one not presenting with
53
comorbidities. She suffered disorientation and somnolence followed by an elongated period of
54
memory and speech difficulties. The authors of this study cautioned clinicians to be aware of
55
USUV in areas where it may be endemic in the avian population and ensure cases be properly
56
vetted regardless of immunological competency.
57
The identification of these cases, while concerning, may not justify the initiation of widespread
58
surveillance and research efforts. The sporadic nature of these cases and the strong association
59
with co-morbidities suggest they are outliers and not part of the natural circulation patterns of
60
this virus. However, a new study by Grottola et al. (7) may change this viewpoint and increase
61
the pressure to initiate more concentrated surveillance and research efforts.
62
A retrospective survey of USUV RNA and USUV-specific antibodies was performed on 915
63
serum and CSF samples collected from 2008-2009 in an area where USUV is endemic in the
AC C
EP
TE D
M AN U
SC
RI PT
42
ACCEPTED MANUSCRIPT
avian population. Viral RNA was detected in the CSF of eight out of 306 samples. Further
65
inspection of available medical history records revealed these patients had suffered either
66
meningoencephalitis or acute encephalitis and suffered other co-morbidities such as chronic liver
67
disease, chronic obstructive pulmonary disease, hypertension, and aortic and mitral insufficiency.
68
Neutralizing antibodies were detected in 6.57% of serum samples although no medical history
69
was provided.
70
Sequence analysis of the isolated USUV RNA revealed high homology to the original South
71
African isolate. Yet several adaptive mutations were detected. This divergence aligns with
72
previous studies examining post-2001 European reference USUV isolates. There was, however,
73
no discussion of the functional impact of these adaptations. This information would have been
74
helpful in determining whether gain of function mutations were present. For example, Gaibani et
75
al. (8) revealed several potential functional mutations in the 2009 blood isolate (3). In particular,
76
a single amino acid change in the NS5 RNA-dependent RNA polymerase domain appeared to
77
increase replicative efficiency.
78
The results of these investigations into USUV suggest a modest increase in prevalence of the
79
virus in the European population. There also is evidence of an increased risk of adaptation for
80
improved fitness in the human host. Though some still may argue there is not yet enough reason
81
to prioritize this virus as a public health threat, the evidence to date suggests this virus is gearing
82
up to be ready for prime time attention.
83
As to when this virus may join the ranks of Zika in terms of public awareness, no one can tell.
84
The virus may undergo adaptive evolution to gain a better hold of the human host. Alternatively,
85
the virus may gain access to a susceptible population leading to outbreaks and a possible
AC C
EP
TE D
M AN U
SC
RI PT
64
ACCEPTED MANUSCRIPT
epidemic. Yet, the virus also may never gain the ability to cause significant morbidity in humans
87
and remain a viral opportunistic infection.
88
In light of the recent experience with ZIKV, the research on USUV to date implies a need for
89
greater attention to this virus moving forward. We may wish to examine rapid methods for
90
diagnostics, gain a greater understanding of the potential for sequelae in individuals, initiate
91
research into treatment options, and determine whether a quest for a vaccine is worthwhile.
92
Although the current trends of research and clinical prioritization suggest we may never know if
93
this is a worthwhile endeavor, we can agree that the more we prepare for it, the less likely we
94
will be to be taken off guard.
95
REFERENCES
96
1. Ashraf U, Ye J, Ruan X, Wan S, Zhu B, Cao S. Usutu virus: an emerging flavivirus in Europe.
97
Viruses. 2015;7(1):219-38.
98
2. Weissenbock H, Kolodziejek J, Url A, Lussy H, Rebel-Bauder B, Nowotny N. Emergence of
99
Usutu virus, an African mosquito-borne flavivirus of the Japanese encephalitis virus group,
TE D
M AN U
SC
RI PT
86
central Europe. Emerg Infect Dis. 2002;8(7):652-6.
101
3. Cavrini F, Gaibani P, Longo G, Pierro AM, Rossini G, Bonilauri P, et al. Usutu virus infection
102
in a patient who underwent orthotropic liver transplantation, Italy, August-September 2009. Euro
103
Surveill. 2009;14(50):17-8.
104
4. Pecorari M, Longo G, Gennari W, Grottola A, Sabbatini A, Tagliazucchi S, et al. First human
105
case of Usutu virus neuroinvasive infection, Italy, August-September 2009. Euro Surveill.
106
2009;14(50):15-6.
AC C
EP
100
ACCEPTED MANUSCRIPT
5. Gaibani P, Pierro A, Alicino R, Rossini G, Cavrini F, Landini MP, et al. Detection of Usutu-
108
virus-specific IgG in blood donors from northern Italy. Vector Borne Zoonotic Dis.
109
2012;12(5):431-3.
110
6. Santini M, Vilibic-Cavlek T, Barsic B, Barbic L, Savic V, Stevanovic V, et al. First cases of
111
human Usutu virus neuroinvasive infection in Croatia, August-September 2013: clinical and
112
laboratory features. J Neurovirol. 2015;21(1):92-7.
113
7. Grottola A, Marcacci M, Tagliazucchi S, Gennari W, Di Gennaro A, Orsini M, et al. Usutu
114
virus infections in humans: a retrospective analysis in the municipality of Modena, Italy. Clin
115
Microbiol Infect. 2017;23(1):33-7.
116
8. Gaibani P, Cavrini F, Gould EA, Rossini G, Pierro A, Landini MP, et al. Comparative
117
genomic and phylogenetic analysis of the first Usutu virus isolate from a human patient
118
presenting with neurological symptoms. PLoS One. 2013;8(5):e64761.
SC
M AN U
TE D EP AC C
119
RI PT
107
S1286-4579(17)30086-2
DOI:
10.1016/j.micinf.2017.05.004
Reference:
MICINF 4474
To appear in:
Microbes and Infection
Received Date: 22 May 2017 Accepted Date: 30 May 2017
Please cite this article as: J.A. Tetro, Is Usutu Virus Ready For Prime Time?, Microbes and Infection (2017), doi: 10.1016/j.micinf.2017.05.004. 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
Commentary
1
2
RI PT
3
4
Is Usutu Virus Ready For Prime Time?
SC
5
M AN U
6
7
Author
8
Jason A. Tetro, B.Sc.
9
13
14
15 16 17 18
19
EP
12
AC C
11
TE D
10
College of Biological Sciences, University of Guelph Guelph, Ontario, N1G 2W1 [email protected]
ACCEPTED MANUSCRIPT
Mosquito-borne viruses have gained significant attention recently thanks in part to the
21
emergence of the Zika virus (ZIKV) in the Americas. Unfortunately, these infectious agents for
22
the most part have been neglected in the larger public health and research communities. This has
23
resulted in a gap of knowledge on various aspects of infection including pathogenesis, tissue
24
tropism, and the impact of co-morbidities. The research surge in research on ZIKV has provided
25
us with a better understanding of the mechanisms behind the development of symptoms such as
26
microcephaly, Guillain-Barré syndrome, and meningoencephalitis. Yet, we can neither deny the
27
extent by which public health researchers and officials were taken off guard nor ignore the need
28
to continue catching up to other viruses as they continue to spread.
29
Dealing with neglected diseases is difficult at best as limited resources purport a need for
30
research and surveillance prioritization. Though some fifteen-hundred pathogens exist
31
worldwide, there are not enough funds to study them all in a translational manner. This leads to
32
gaps in knowledge and ultimately, treatment options. Additionally, surveillance provides
33
perspective on the relative risk certain pathogens portend. Yet these activities may offer little to
34
no valuable return.
35
One such example of an emerging neglected disease caught in this conundrum is Usutu virus
36
(USUV). Although the name still is relatively obscure in public health sectors, its history and
37
biology have been known for some time (1). This member of the Flavivirus family, first
38
discovered in 1959 in South Africa, circulates in several mosquito species, and infects both avian
39
and mammalian hosts. The virus has since spread into Europe (2) and is considered endemic in
40
certain Central and Eastern regions of the continent. Yet the threat to human health in these areas
41
has not been fully elucidated.
AC C
EP
TE D
M AN U
SC
RI PT
20
ACCEPTED MANUSCRIPT
The first cases of USUV human infection in Europe were documented in 2009 when virus was
43
isolated from blood (3) and viral RNA was detected in cerebrospinal fluid (CSF) (4) of
44
immunocompromised patients in Italy. The find led researchers in these cases to suggest USUV
45
may have evolved such that it could infect humans. However, due to the frail immunity of the
46
patients, the potential for outbreaks in immunocompetent populations was considered to be
47
unlikely. Supporting this assessment was a study by Gaibani et al (5), who performed a survey of
48
359 Italian blood donors. Only four revealed USUV-specific antibodies with no evidence of
49
symptoms.
50
The only case in which an immunocompetent individual presented with neurological defects with
51
USUV infection occurred in Croatia in 2013 in Croatia (6). The twenty-nine year old patient was
52
one of three cases discovered during this time but was the only one not presenting with
53
comorbidities. She suffered disorientation and somnolence followed by an elongated period of
54
memory and speech difficulties. The authors of this study cautioned clinicians to be aware of
55
USUV in areas where it may be endemic in the avian population and ensure cases be properly
56
vetted regardless of immunological competency.
57
The identification of these cases, while concerning, may not justify the initiation of widespread
58
surveillance and research efforts. The sporadic nature of these cases and the strong association
59
with co-morbidities suggest they are outliers and not part of the natural circulation patterns of
60
this virus. However, a new study by Grottola et al. (7) may change this viewpoint and increase
61
the pressure to initiate more concentrated surveillance and research efforts.
62
A retrospective survey of USUV RNA and USUV-specific antibodies was performed on 915
63
serum and CSF samples collected from 2008-2009 in an area where USUV is endemic in the
AC C
EP
TE D
M AN U
SC
RI PT
42
ACCEPTED MANUSCRIPT
avian population. Viral RNA was detected in the CSF of eight out of 306 samples. Further
65
inspection of available medical history records revealed these patients had suffered either
66
meningoencephalitis or acute encephalitis and suffered other co-morbidities such as chronic liver
67
disease, chronic obstructive pulmonary disease, hypertension, and aortic and mitral insufficiency.
68
Neutralizing antibodies were detected in 6.57% of serum samples although no medical history
69
was provided.
70
Sequence analysis of the isolated USUV RNA revealed high homology to the original South
71
African isolate. Yet several adaptive mutations were detected. This divergence aligns with
72
previous studies examining post-2001 European reference USUV isolates. There was, however,
73
no discussion of the functional impact of these adaptations. This information would have been
74
helpful in determining whether gain of function mutations were present. For example, Gaibani et
75
al. (8) revealed several potential functional mutations in the 2009 blood isolate (3). In particular,
76
a single amino acid change in the NS5 RNA-dependent RNA polymerase domain appeared to
77
increase replicative efficiency.
78
The results of these investigations into USUV suggest a modest increase in prevalence of the
79
virus in the European population. There also is evidence of an increased risk of adaptation for
80
improved fitness in the human host. Though some still may argue there is not yet enough reason
81
to prioritize this virus as a public health threat, the evidence to date suggests this virus is gearing
82
up to be ready for prime time attention.
83
As to when this virus may join the ranks of Zika in terms of public awareness, no one can tell.
84
The virus may undergo adaptive evolution to gain a better hold of the human host. Alternatively,
85
the virus may gain access to a susceptible population leading to outbreaks and a possible
AC C
EP
TE D
M AN U
SC
RI PT
64
ACCEPTED MANUSCRIPT
epidemic. Yet, the virus also may never gain the ability to cause significant morbidity in humans
87
and remain a viral opportunistic infection.
88
In light of the recent experience with ZIKV, the research on USUV to date implies a need for
89
greater attention to this virus moving forward. We may wish to examine rapid methods for
90
diagnostics, gain a greater understanding of the potential for sequelae in individuals, initiate
91
research into treatment options, and determine whether a quest for a vaccine is worthwhile.
92
Although the current trends of research and clinical prioritization suggest we may never know if
93
this is a worthwhile endeavor, we can agree that the more we prepare for it, the less likely we
94
will be to be taken off guard.
95
REFERENCES
96
1. Ashraf U, Ye J, Ruan X, Wan S, Zhu B, Cao S. Usutu virus: an emerging flavivirus in Europe.
97
Viruses. 2015;7(1):219-38.
98
2. Weissenbock H, Kolodziejek J, Url A, Lussy H, Rebel-Bauder B, Nowotny N. Emergence of
99
Usutu virus, an African mosquito-borne flavivirus of the Japanese encephalitis virus group,
TE D
M AN U
SC
RI PT
86
central Europe. Emerg Infect Dis. 2002;8(7):652-6.
101
3. Cavrini F, Gaibani P, Longo G, Pierro AM, Rossini G, Bonilauri P, et al. Usutu virus infection
102
in a patient who underwent orthotropic liver transplantation, Italy, August-September 2009. Euro
103
Surveill. 2009;14(50):17-8.
104
4. Pecorari M, Longo G, Gennari W, Grottola A, Sabbatini A, Tagliazucchi S, et al. First human
105
case of Usutu virus neuroinvasive infection, Italy, August-September 2009. Euro Surveill.
106
2009;14(50):15-6.
AC C
EP
100
ACCEPTED MANUSCRIPT
5. Gaibani P, Pierro A, Alicino R, Rossini G, Cavrini F, Landini MP, et al. Detection of Usutu-
108
virus-specific IgG in blood donors from northern Italy. Vector Borne Zoonotic Dis.
109
2012;12(5):431-3.
110
6. Santini M, Vilibic-Cavlek T, Barsic B, Barbic L, Savic V, Stevanovic V, et al. First cases of
111
human Usutu virus neuroinvasive infection in Croatia, August-September 2013: clinical and
112
laboratory features. J Neurovirol. 2015;21(1):92-7.
113
7. Grottola A, Marcacci M, Tagliazucchi S, Gennari W, Di Gennaro A, Orsini M, et al. Usutu
114
virus infections in humans: a retrospective analysis in the municipality of Modena, Italy. Clin
115
Microbiol Infect. 2017;23(1):33-7.
116
8. Gaibani P, Cavrini F, Gould EA, Rossini G, Pierro A, Landini MP, et al. Comparative
117
genomic and phylogenetic analysis of the first Usutu virus isolate from a human patient
118
presenting with neurological symptoms. PLoS One. 2013;8(5):e64761.
SC
M AN U
TE D EP AC C
119
RI PT
107