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Obesity's Unexpected Influence: Reduced Alphavirus Transmission and Altered Immune Activation in the Vector
Pallavi Rai1,2, Emily M Webb2,3, Sally L Paulson3
1Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.
Abstract:
Chikungunya virus (CHIKV) and Mayaro virus (MAYV) are emerging/re-emerging alphaviruses transmitted by Aedes spp. mosquitoes and responsible for recent disease outbreaks in the Americas. The capacity of these viruses to cause epidemics is frequently associated with increased mosquito transmission, which in turn is governed by virus-host-vector interactions. Although many studies have explored virus-vector interactions, significant gaps remain in understanding how vertebrate host factors influence alphavirus transmission by mosquitoes. We previously showed that obesity, a ubiquitous vertebrate host biological factor, reduces alphavirus transmission potential in mosquitoes. We hypothesized that alphavirus-infected obese bloodmeals altered immune genes and/or pathways in mosquitoes, thereby inhibiting virus transmission. To test this, we conducted RNA sequencing (RNA-seq) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) on midgut RNA from mosquitoes fed on alphavirus-infected lean and obese mice. This approach aimed to identify potential antiviral or proviral genes and pathways altered in mosquitoes after consuming infected obese bloodmeals. We found upregulation of the Toll pathway and downregulation of several metabolic and other genes in mosquitoes fed on alphavirus-infected obese bloodmeals. Through gene knockdown studies, we demonstrated the antiviral role of Toll pathway and proviral roles of AAEL009965 and fatty acid synthase (FASN) in the transmission of alphaviruses by mosquitoes. Therefore, this study utilized obesity to identify factors influencing alphavirus transmission by mosquitoes and this research approach may pave the way for designing broadly effective antiviral measures to combat mosquito-borne viruses, such as releasing transgenic mosquitoes deficient in the identified genes.
Insights
Obesity in vertebrate hosts impacts mosquito-borne alphavirus transmission by altering mosquito immune and metabolic genes. Identifying these host-dependent factors may lead to new antiviral strategies against viruses like Chikungunya virus (CHIKV) and Mayaro virus (MAYV).
Area of Science:
- Virology
- Immunology
- Entomology
- Genetics
Background:
- Chikungunya virus (CHIKV) and Mayaro virus (MAYV) are significant alphaviruses causing outbreaks in the Americas, transmitted by Aedes mosquitoes.
- Virus-host-vector interactions are crucial for epidemic potential, yet host factors influencing alphavirus transmission remain understudied.
- Previous research indicated that host obesity reduces alphavirus transmission by mosquitoes.
Purpose of the Study:
- To investigate how alphavirus-infected obese bloodmeals alter mosquito immune genes and pathways, inhibiting virus transmission.
- To identify specific genes and pathways in mosquitoes that influence alphavirus transmission.
- To explore the potential for novel antiviral strategies based on host-dependent transmission factors.
Main Methods:
- RNA sequencing (RNA-seq) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to analyze midgut RNA from mosquitoes fed on infected lean and obese mouse bloodmeals.
- Gene knockdown studies were performed to validate the roles of identified genes in alphavirus transmission.
- Comparative analysis of gene expression profiles between mosquitoes fed on lean versus obese bloodmeals.
Main Results:
- Mosquitoes fed on alphavirus-infected obese bloodmeals showed upregulation of the Toll pathway and downregulation of metabolic genes.
- Gene knockdown confirmed the Toll pathway's antiviral role in alphavirus transmission.
- AAEL009965 and fatty acid synthase (FASN) were identified as having proviral roles in alphavirus transmission.
Conclusions:
- Host obesity influences mosquito immune gene expression, impacting alphavirus transmission.
- The Toll pathway acts antagonistically to alphavirus transmission, while AAEL009965 and FASN promote it.
- This research provides a framework for developing broad-spectrum antivirals against mosquito-borne viruses by targeting identified host-dependent factors, potentially through genetically modified mosquitoes.
