Doctor of Philosophy, Yale University (2019)
Bachelor of Science, Zhejiang University (2013)
Lymph-borne Friend murine leukemia virus (FrMLV) exploits the sentinel macrophages in the draining popliteal lymph node (pLN) to infect highly permissive innate-like B-1 cells and establish infection in mice. The reason for FrMLV sensitivity of B-1 cells and their impact on viral spread is unknown. Here we demonstrate that Toll-like receptor 7 (TLR7) sensing and type I interferon (IFN-I) signaling in B-1 cells contribute to FrMLV susceptibility. FrMLV infection in B-1 cell-deficient mice (bumble; I?BNS dysfunctional) was significantly lower than that in the wild-type mice and was rescued by adoptive transfer of wild-type B-1 cells. This rescue of FrMLV infection in bumble mice was dependent on intact TLR7 sensing and IFN-I signaling within B-1 cells. Analyses of infected cell types revealed that the reduced infection in bumble mice was due predominantly to compromised virus spread to the B-2 cell population. Our data reveal how FrMLV exploits innate immune sensing and activation in the B-1 cell population for infection and subsequent spread to other lymphocytes.IMPORTANCE Viruses establish infection in hosts by targeting highly permissive cell types. The retrovirus Friend murine leukemia virus (FrMLV) infects a subtype of B cells called B-1 cells that permit robust virus replication. The reason for their susceptibility had remained unknown. We found that innate sensing of incoming virus and the ensuing type I interferon response within B-1 cells are responsible for their observed susceptibility. Our data provide insights into how retroviruses coevolved with the host to co-opt innate immune sensing pathways designed to fight virus infections for establishing infection. Understanding early events in viral spread can inform antiviral intervention strategies that prevent the colonization of a host.
View details for DOI 10.1128/JVI.00930-19
View details for Web of Science ID 000490259000019
View details for PubMedID 31434732
View details for PubMedCentralID PMC6803250
Lymph- and blood-borne retroviruses exploit CD169/Siglec-1-mediated capture by subcapsular sinus and marginal zone metallophilic macrophages for trans-infection of permissive lymphocytes. However, the impact of CD169-mediated virus capture on retrovirus dissemination and pathogenesis inávivo is unknown. In a murine model of the splenomegaly-inducing retrovirus Friend virus complex (FVC) infection, we find that while CD169 promoted draining lymph node infection, it limited systemic spread to the spleen. At the spleen, CD169-expressing macrophages captured incoming blood-borne retroviruses and limited their spread to the erythroblasts in the red pulp where FVC manifests its pathogenesis. CD169-mediated retroviral capture activated conventional dendritic cells 1 (cDC1s) and promoted cytotoxic CD8+ Tácell responses, resulting in efficient clearing of FVC-infected cells. Accordingly, CD169 blockade led to higher viral loads and accelerated death in susceptible mouse strains. Thus, CD169 plays a protective role during FVC pathogenesis by reducing viral dissemination to erythroblasts and eliciting an effective cytotoxic T lymphocyte response via cDC1s.
View details for DOI 10.1016/j.chom.2018.11.011
View details for Web of Science ID 000455216900012
View details for PubMedID 30595553
View details for PubMedCentralID PMC6331384
Viruses are causative agents for many diseases and infect all living organisms on the planet. Development of effective therapies has relied on our ability to isolate and culture viruses in vitro, allowing mechanistic studies and strategic interventions. While this reductionist approach is necessary, testing the relevance of in vitro findings often takes a very long time. New developments in imaging technologies are transforming our experimental approach where viral pathogenesis can be studied in vivo at multiple spatial and temporal resolutions. Here, we outline a vision of a top-down approach using noninvasive whole-body imaging as a guide for in-depth characterization of key tissues, physiologically relevant cell types, and pathways of spread to elucidate mechanisms of virus spread and pathogenesis. Tool development toward imaging of infectious diseases is expected to transform clinical diagnosis and treatment.
View details for DOI 10.1146/annurev-virology-101416-041429
View details for Web of Science ID 000488796700024
View details for PubMedID 31283440
View details for DOI 10.1177/1535676018785177
Fungus-cultivating termites (Macrotermitinae) possess an elaborate strategy of lignocellulose digestion. It involves a lignocellulose-degrading fungal symbiont (genus Termitomyces), a diverse gut microbiota and a characteristic labour division in food processing. In this study, using pyrotag sequencing and electron microscopy, we analysed the bacterial microbiota in the hindgut of Odontotermes formosanus and its fungus comb to investigate the spatial organization, establishment and temporal succession of the bacterial communities colonizing specific microhabitats. Our results document strong differences between the communities at the hindgut epithelium and the luminal fluid of newly moulted, young and old worker termites. The differences in community structure were consistent with the density, morphology and spatial distribution of bacterial cells and the pools of microbial metabolites in the hindgut compartment, underlining that both gut development and the age-specific changes in diet affect the composition and functional role of their gut microbiota. These findings provide strong support for the concept that changes in diet and gut environment are important determinants of community structure because they create new niches for microbial symbionts.
View details for DOI 10.1111/1462-2920.13046
View details for Web of Science ID 000375481200014
View details for PubMedID 26346907
Dendritic cells can capture and transfer retroviruses in vitro across synaptic cell-cell contacts to uninfected cells, a process called trans-infection. Whether trans-infection contributes to retroviral spread in vivo remains unknown. Here, we visualize how retroviruses disseminate in secondary lymphoid tissues of living mice. We demonstrate that murine leukemia virus (MLV) and human immunodeficiency virus (HIV) are first captured by sinus-lining macrophages. CD169/Siglec-1, an I-type lectin that recognizes gangliosides, captures the virus. MLV-laden macrophages then form long-lived synaptic contacts to trans-infect B-1 cells. Infected B-1 cells subsequently migrate into the lymph node to spread the infection through virological synapses. Robust infection in lymph nodes and spleen requires CD169, suggesting that a combination of fluid-based movement followed by CD169-dependent trans-infection can contribute to viral spread.
View details for DOI 10.1126/science.aab2749
View details for Web of Science ID 000363660000049
View details for PubMedID 26429886
View details for PubMedCentralID PMC4651917
A novel anaerobic bacterium, designated NH-JN4(T) was isolated from a sediment sample collected in the South China Sea. Cells were Gram-stain-positive, spore-forming, peritrichous and rod-shaped (0.5-1.2Î2.2-7 Ám). The temperature and pH ranges for growth were 22-42 ░C and pH 6.0-8.5. Optimal growth occurred at 34-38 ░C and pH 6.5-7.0. The NaCl concentration range for growth was 0.5-6?% (w/v) with an optimum of 2.5?%. Catalase and oxidase were not produced. Substrates which could be utilized were peptone, tryptone, yeast extract, beef extract and glycine. Main fermentation products from PYG medium were formate, acetate, butyrate and ethanol. Strain NH-JN4(T) could utilize sodium sulfite as an electron acceptor. No respiratory quinone was detected. The predominant fatty acids were anteiso-C15?:?0, C16?:?0, iso-C15?:?0, anteiso-C17?:?0 and C16?:?0 DMA. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and glycolipids. The DNA G+C content was 35.8 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain NH-JN4(T) was a member of family Clostridiaceae, and was most closely related to Clostridium limosum ATCC 25620(T), Clostridium proteolyticum DSM 3090(T), Clostridium histolyticum ATCC 19401(T) and Clostridium tepidiprofundi SG 508(T), showing 94.0, 93.0, 92.9 and 92.3?% sequence similarity, respectively. On the basis of phenotypic, genotypic and chemotaxonomic properties, strain NH-JN4(T) represents a novel species of a new genus in the family Clostridiaceae, for which the name Oceanirhabdus sediminicola gen. nov., sp. nov. is proposed. The type strain of the type species is NH-JN4(T) (?=?JCM 18501(T)?=?CCTCC AB 2013103(T)?=?KCTC 15322(T)).
View details for DOI 10.1099/ijs.0.051243-0
View details for Web of Science ID 000328666600055
View details for PubMedID 23811141