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A Single Substitution Changes Zika Virus Infectivity in Mosquitoes
TIMI 1471 No. of Pages 2
Spotlight
A Single Substitution Changes Zika Virus Infectivity in Mosquitoes Guan-Zhu Han1,* Zika virus (ZIKV) has caused outbreaks in the Pacific and the Americas. The mechanism underlying the recent ZIKV epidemic remains obscure. A recent study reveals that an amino acid substitution is associated with increased infectivity of ZIKV in the Aedes aegypti mosquito.
ZIKV, a mosquito-borne flavivirus closely related to dengue virus and yellow fever virus, has posed a great threat to global public health recently [1]. ZIKV infection has been implicated in several neurologic disorders, such as Guillain– Barré syndrome and microcephaly [1]. Detected sporadically in Africa and Asia and largely neglected before 2007, when a ZIKV outbreak was reported in Micronesia [1], ZIKV has spread to and caused outbreaks in the Pacific (2013–2014) and the Americas (2015–2016). Evolutionary analyses reveal that ZIKV evolved into three major lineages, namely the Asian, African I, and African II lineages [2]. The African II lineage is a sister group to the Asian and African I lineages. The recent ZIKV epidemic in the Americas was caused by a single introduction of the Asian lineage around 2013 [3]. However, little is known about the molecular mechanism underlying the recent geographic expansion of ZIKV. Recent research by Liu et al. [4] reported that an amino acid substitution is associated with increased infectivity of the ZIKV strain responsible for the epidemic in the Americas in the mosquito vector Ae. aegypti.
Liu et al. [4] found significantly higher infectivity in a strain (GZ01, isolated from a returning Chinese traveler from Venezuela in 2016) associated with the recent American outbreak than in a strain (FSS13025, isolated Cambodia 2010) circulating in Southeast Asia in the mosquito vector Ae. aegypti. The authors show that the ZIKV infectivity in Ae. aegypti was linked to the secretability of nonstructural protein 1 (NS1). They further identified an alanine-to-valine amino acid substitution at residue 188 (A188V) in NS1 determining the secretability of NS1. They introduced A188V substitution into the FSS13025 strain, which substantially increased the secretion of NS1 and its infectivity in Ae. aegypti. In addition to strains isolated in America, they found that the 188V residue exists in all the strains of African I lineages, and one of them, the MR766 strain isolated in Uganda in 1947, secreted abundant NS1. This study provides a clear example of functional adaptation of ZIKV to the mosquito vector Ae. aegypti. When and where did the A188V substitution appear? The residue 188 in isolates of Asian lineage collected before 2012, and of African I lineage, is alanine, but this residue in isolates of Asian lineage collected after 2014 is valine. This residue remains unclear in the isolates of African II lineage, because no complete genome of this lineage has been available to date. The homologous residue in Spondweni virus, the closet relative of ZIKV, is valine [5]. Based on the aforementioned information, we reconstructed the evolutionary history of residue 188 in ZIKV (Figure 1). The ancestral state of this residue in ZIKV is valine. It evolved into alanine [5_TD$IF]during the spread of ZIKV to Southeast Asia. The reversion to valine appeared in Southeast Asia (before node a in Figure 1, which corresponds to no later than 2011 [6]). Residue 188 in the two strains isolated in Southeast Asia in 2010 and 2012 is alanine, suggesting that strains with 188A and 188V might have coexisted for some time. Residue 188 in
all the strains isolated in Southeast Asia after 2014 is valine [4,6]. Therefore, it seems unlikely that strains with 188A currently remain circulating in Southeast Asia. But this conclusion should be taken with caution, because only a limited number of sequences are currently available for ZIKV strains isolated in Southeast Asia. To date, the sequencing effort has mainly focused on the American strains (hundreds of genomes of American strains vs. four genomes of Southeast Asian strains) [7,8]. However, we believe that sequencing more Asian strains [6] and African strains would provide a valuable resource for tracking the evolutionary history of ZIKV and identifying key adaptations in ZIKV. The strains with 188A spread to Micronesia in the western Pacific in 2007 but failed to go beyond. In contrast, the strains with A188V spread far beyond and to the Americas. This raises the hypothesis that the A188V substitution contributed to the recent emergence of ZIKV [4]. However, the A188V substitution appears not to be selected to improve the ability to spread, given that this substitution arose and became fixed (if this is the case) in Southeast Asia. Therefore, it is still difficult to establish a causal relationship between the A188V substitution and the geographic expansion of ZIKV. Why did the residue 188 mutate [56_TD$IF]back and forth between alanine and valine? This actually encompasses two questions. First, why did V188A appear [57_TD$IF]during the spread of ZIKV to Southeast Asia? Second, why did A188V reappear in Southeast Asia? A previous study shows that a single mutation in the envelope protein (A226V) of [58_TD$IF]chikungunya virus (CHIKV), another mosquito-borne flavivirus, increased the infectivity of CHIKV in Aedes albopictus but caused a decrease in CHIKV infectivity in Ae. aegypti [9]. This mutation was associated with the epidemic of CHIKV on Reunion Island in 2005–2006 [9]. It is possible that different amino acids at residue 188 are associated with differences in vector specificity,
Trends in Microbiology, Month Year, Vol. xx, No. yy
1
TIMI 1471 No. of Pages 2
188
A
V
Pacific islands & Americas
V
Singapore 2016
V
a
V
A
Asian
Thailand 2014
V
Cambodia 2010
A
Philippines 2012
A
Micronesia 2007
A
Malaysia 1966
A
African I
Africa
Spondweni virus
V
V
Figure 1. The Evolutionary History of Zika Virus (ZIKV). The phylogenetic tree is based on [3,4,6–8]. The amino acids at residue 188 are indicated in the right panel. The occurrences of V188A and A188V are labeled in the corresponding branches. The time of node a corresponds to no later than 2011 [6].
and that residue 188 evolved with a Acknowledgments change in the composition of vectors. G.-Z.H. was supported by the Natural Science FounThe ZIKV strain with 188A exhibits lower dation of Jiangsu Province (BK20161016) and the infectivity in Ae. aegypti, which does not Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions. necessarily mean lower infectivity in all the other mosquito vectors. Otherwise, it 1Jiangsu Key Laboratory for Microbes and Functional would not have circulated in Southeast Genomics, Jiangsu Engineering and Technology Research Center for Microbiology, College of Life Sciences, Nanjing Asia for more than 46 years. Neverthe- Normal University, Nanjing, Jiangsu 210046, China less, following the standard set by Liu et al[59_TD$IF]. [4], much work (such as exploring the *Correspondence: [email protected] (G.-Z. Han). effect of different amino acids at residue http://dx.doi.org/10.1016/j.tim.2017.05.014 188 on ZIKV infectivity in different mosquito vectors[60_TD$IF]) is needed to resolve these References questions and to reveal more details 1. Broutet, N. et al. (2016) Zika virus as a cause of neurologic disorders. N. Engl. J. Med. 374, 1506–1509 about molecular adaptations along the 2. Gong, Z. et al. (2016) Zika virus: two or three lineages? evolutionary history of ZIKV. Trends Microbiol. 24, 521–522
2
Trends in Microbiology, Month Year, Vol. xx, No. yy
3. Faria, N.R. et al. (2016) Zika virus in the Americas: early epidemiological and genetic findings. Science 352, 345–359 4. Liu, Y. et al. (2017) Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes. Nature 545, 482–486 5. Grard, G. et al. (2010) Genomics and evolution of Aedesborne flaviviruses. J. Gen. Virol. 91, 87–94 6. Singapore Zika Study Group (2017) Outbreak of Zika virus infection in Singapore: an epidemiological, entomological, virological, and clinical analysis. Lancet Infect. Dis. Published online May 17, 2017. http://dx.doi.org/10.1016/ S1473-3099(17)30249-9 7. Metsky, H.C. et al. (2017) Zika virus evolution and spread in the Americas. Nature Published online May 24, 2017. http:// dx.doi.org/10.1038/nature22402 8. Faria, N.R. et al. (2017) Establishment and cryptic transmission of Zika virus in Brazil and the Americas. Nature Published online May 24, 2017. http://dx.doi.org/10.1038/ nature22401 9. Tsetsarkin, K.A. et al. (2007) A single mutation in Chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog. 3, e201
Spotlight
A Single Substitution Changes Zika Virus Infectivity in Mosquitoes Guan-Zhu Han1,* Zika virus (ZIKV) has caused outbreaks in the Pacific and the Americas. The mechanism underlying the recent ZIKV epidemic remains obscure. A recent study reveals that an amino acid substitution is associated with increased infectivity of ZIKV in the Aedes aegypti mosquito.
ZIKV, a mosquito-borne flavivirus closely related to dengue virus and yellow fever virus, has posed a great threat to global public health recently [1]. ZIKV infection has been implicated in several neurologic disorders, such as Guillain– Barré syndrome and microcephaly [1]. Detected sporadically in Africa and Asia and largely neglected before 2007, when a ZIKV outbreak was reported in Micronesia [1], ZIKV has spread to and caused outbreaks in the Pacific (2013–2014) and the Americas (2015–2016). Evolutionary analyses reveal that ZIKV evolved into three major lineages, namely the Asian, African I, and African II lineages [2]. The African II lineage is a sister group to the Asian and African I lineages. The recent ZIKV epidemic in the Americas was caused by a single introduction of the Asian lineage around 2013 [3]. However, little is known about the molecular mechanism underlying the recent geographic expansion of ZIKV. Recent research by Liu et al. [4] reported that an amino acid substitution is associated with increased infectivity of the ZIKV strain responsible for the epidemic in the Americas in the mosquito vector Ae. aegypti.
Liu et al. [4] found significantly higher infectivity in a strain (GZ01, isolated from a returning Chinese traveler from Venezuela in 2016) associated with the recent American outbreak than in a strain (FSS13025, isolated Cambodia 2010) circulating in Southeast Asia in the mosquito vector Ae. aegypti. The authors show that the ZIKV infectivity in Ae. aegypti was linked to the secretability of nonstructural protein 1 (NS1). They further identified an alanine-to-valine amino acid substitution at residue 188 (A188V) in NS1 determining the secretability of NS1. They introduced A188V substitution into the FSS13025 strain, which substantially increased the secretion of NS1 and its infectivity in Ae. aegypti. In addition to strains isolated in America, they found that the 188V residue exists in all the strains of African I lineages, and one of them, the MR766 strain isolated in Uganda in 1947, secreted abundant NS1. This study provides a clear example of functional adaptation of ZIKV to the mosquito vector Ae. aegypti. When and where did the A188V substitution appear? The residue 188 in isolates of Asian lineage collected before 2012, and of African I lineage, is alanine, but this residue in isolates of Asian lineage collected after 2014 is valine. This residue remains unclear in the isolates of African II lineage, because no complete genome of this lineage has been available to date. The homologous residue in Spondweni virus, the closet relative of ZIKV, is valine [5]. Based on the aforementioned information, we reconstructed the evolutionary history of residue 188 in ZIKV (Figure 1). The ancestral state of this residue in ZIKV is valine. It evolved into alanine [5_TD$IF]during the spread of ZIKV to Southeast Asia. The reversion to valine appeared in Southeast Asia (before node a in Figure 1, which corresponds to no later than 2011 [6]). Residue 188 in the two strains isolated in Southeast Asia in 2010 and 2012 is alanine, suggesting that strains with 188A and 188V might have coexisted for some time. Residue 188 in
all the strains isolated in Southeast Asia after 2014 is valine [4,6]. Therefore, it seems unlikely that strains with 188A currently remain circulating in Southeast Asia. But this conclusion should be taken with caution, because only a limited number of sequences are currently available for ZIKV strains isolated in Southeast Asia. To date, the sequencing effort has mainly focused on the American strains (hundreds of genomes of American strains vs. four genomes of Southeast Asian strains) [7,8]. However, we believe that sequencing more Asian strains [6] and African strains would provide a valuable resource for tracking the evolutionary history of ZIKV and identifying key adaptations in ZIKV. The strains with 188A spread to Micronesia in the western Pacific in 2007 but failed to go beyond. In contrast, the strains with A188V spread far beyond and to the Americas. This raises the hypothesis that the A188V substitution contributed to the recent emergence of ZIKV [4]. However, the A188V substitution appears not to be selected to improve the ability to spread, given that this substitution arose and became fixed (if this is the case) in Southeast Asia. Therefore, it is still difficult to establish a causal relationship between the A188V substitution and the geographic expansion of ZIKV. Why did the residue 188 mutate [56_TD$IF]back and forth between alanine and valine? This actually encompasses two questions. First, why did V188A appear [57_TD$IF]during the spread of ZIKV to Southeast Asia? Second, why did A188V reappear in Southeast Asia? A previous study shows that a single mutation in the envelope protein (A226V) of [58_TD$IF]chikungunya virus (CHIKV), another mosquito-borne flavivirus, increased the infectivity of CHIKV in Aedes albopictus but caused a decrease in CHIKV infectivity in Ae. aegypti [9]. This mutation was associated with the epidemic of CHIKV on Reunion Island in 2005–2006 [9]. It is possible that different amino acids at residue 188 are associated with differences in vector specificity,
Trends in Microbiology, Month Year, Vol. xx, No. yy
1
TIMI 1471 No. of Pages 2
188
A
V
Pacific islands & Americas
V
Singapore 2016
V
a
V
A
Asian
Thailand 2014
V
Cambodia 2010
A
Philippines 2012
A
Micronesia 2007
A
Malaysia 1966
A
African I
Africa
Spondweni virus
V
V
Figure 1. The Evolutionary History of Zika Virus (ZIKV). The phylogenetic tree is based on [3,4,6–8]. The amino acids at residue 188 are indicated in the right panel. The occurrences of V188A and A188V are labeled in the corresponding branches. The time of node a corresponds to no later than 2011 [6].
and that residue 188 evolved with a Acknowledgments change in the composition of vectors. G.-Z.H. was supported by the Natural Science FounThe ZIKV strain with 188A exhibits lower dation of Jiangsu Province (BK20161016) and the infectivity in Ae. aegypti, which does not Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions. necessarily mean lower infectivity in all the other mosquito vectors. Otherwise, it 1Jiangsu Key Laboratory for Microbes and Functional would not have circulated in Southeast Genomics, Jiangsu Engineering and Technology Research Center for Microbiology, College of Life Sciences, Nanjing Asia for more than 46 years. Neverthe- Normal University, Nanjing, Jiangsu 210046, China less, following the standard set by Liu et al[59_TD$IF]. [4], much work (such as exploring the *Correspondence: [email protected] (G.-Z. Han). effect of different amino acids at residue http://dx.doi.org/10.1016/j.tim.2017.05.014 188 on ZIKV infectivity in different mosquito vectors[60_TD$IF]) is needed to resolve these References questions and to reveal more details 1. Broutet, N. et al. (2016) Zika virus as a cause of neurologic disorders. N. Engl. J. Med. 374, 1506–1509 about molecular adaptations along the 2. Gong, Z. et al. (2016) Zika virus: two or three lineages? evolutionary history of ZIKV. Trends Microbiol. 24, 521–522
2
Trends in Microbiology, Month Year, Vol. xx, No. yy
3. Faria, N.R. et al. (2016) Zika virus in the Americas: early epidemiological and genetic findings. Science 352, 345–359 4. Liu, Y. et al. (2017) Evolutionary enhancement of Zika virus infectivity in Aedes aegypti mosquitoes. Nature 545, 482–486 5. Grard, G. et al. (2010) Genomics and evolution of Aedesborne flaviviruses. J. Gen. Virol. 91, 87–94 6. Singapore Zika Study Group (2017) Outbreak of Zika virus infection in Singapore: an epidemiological, entomological, virological, and clinical analysis. Lancet Infect. Dis. Published online May 17, 2017. http://dx.doi.org/10.1016/ S1473-3099(17)30249-9 7. Metsky, H.C. et al. (2017) Zika virus evolution and spread in the Americas. Nature Published online May 24, 2017. http:// dx.doi.org/10.1038/nature22402 8. Faria, N.R. et al. (2017) Establishment and cryptic transmission of Zika virus in Brazil and the Americas. Nature Published online May 24, 2017. http://dx.doi.org/10.1038/ nature22401 9. Tsetsarkin, K.A. et al. (2007) A single mutation in Chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog. 3, e201