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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Animal Parasitic Diseases Laboratory » Research » Publications at this Location » Publication #376854

Research Project: Molecular Approaches to Control Intestinal Parasites that Affect the Microbiome in Swine and Small Ruminants

Location: Animal Parasitic Diseases Laboratory

Title: Enteric helminth coinfection enhances host susceptibility to West Nile virus in the brain via a tuft cell-IL-4Ra signaling axis in gut epithelium

item DESAI, PRITESH - Washington University School Of Medicine
item JANOVA, HANA - Washington University School Of Medicine
item WHITE, JAMES - Washington University School Of Medicine
item REYNOSO, GLENNYS - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item HICKMAN, HEATHER - Washington University School Of Medicine
item BALDRIDGE, MEGAN - Washington University School Of Medicine
item Urban, Joseph
item STAPPENBECK, THADDEUS - Cleveland Clinic
item THACKRAY, LARISSA - Washington University School Of Medicine
item DIAMOND, MICHAEL - Washington University School Of Medicine

Submitted to: Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/25/2021
Publication Date: 3/4/2021
Citation: Desai, P., Janova, H., White, J.P., Reynoso, G.V., Hickman, H.D., Baldridge, M.T., Urban Jr, J.F., Stappenbeck, T.S., Thackray, L.B., Diamond, M.S. 2021. Enteric helminth coinfection enhances host susceptibility to West Nile virus in the brain via a tuft cell-IL-4Ra signaling axis in gut epithelium . Cell.

Interpretive Summary: Parasitic nematodes (worms) that infect livestock reduce production of meat, milk and fiber, and also have deleterious effects on human health in areas of the world were these infections are common in humans. Epidemiological data indicates that areas were worm infections are endemic have higher incidences of co-infections including HIV, malaria, and tuberculosis suggesting that worm infection can impair host immunity against specific classes of pathogens. There is little experimental evidence examining the influence of these worm infections on responses to viruses. The Flavivirus genus is comprised of several RNA viruses of medical importance including Dengue (DENV), Zika (ZIKV), yellow fever (YFV), West Nile (WNV), Japanese encephalitis (JEV), and tick-borne encephalitis (TBEV) viruses that are transmitted principally by insect vectors with a broad geographical range. The interaction between worms and flavivirus co-infection was studied in a mouse model using WNV and the parasitic worm Heligmosomoides polygyrus bakeri (Hpb). Mice co-infected with Hpb and WNV had higher mortality compared to either infection alone with higher viral burden in the brain, spinal cord and gastrointestinal (GI) tract. Tissue and molecular analysis of the GI tract indicated that worm infection activated a specific cell population called the tuft cell through the production of a protein messenger molecule called IL-4 that damages the GI epithelial barrier, resulting in movement of gut bacteria into secondary lymphoid organs and loss of the virus-specific lymphocytes or CD8+ T cells that reduce immunity to the virus. This leads to enhanced WNV infection in the central nervous system that reduces host survival. Co-infection with virus and worms also enhanced susceptibility to ZIKV and POWV in this mouse model suggesting that worms enhance the disease severity of multiple neurotropic flaviviruses. The research indicates that there are mostly negative consequences to dueling infections in the same tissue such as the GI track which is important for both livestock and humans where the incidence of co-infection between intestinal worms and viruses is very likely. The work strongly supports the need for more investigation of these types of co-infection by research scientists and clinicians to reduce debilitating infectious diseases in humans and agricultural animals.

Technical Abstract: Although enteric helminth infections modulate immunity to mucosal pathogens, their effects on immune responses to systemically acquired microbes remain largely unknown. Here, we observed an increased mortality in mice coinfected with the enteric helminth Heligmosomoides polygyrus bakeri (Hpb) and West Nile virus (WNV), associated with altered gut morphology, translocation of commensal bacteria, impaired WNV-specific T cell responses, and increased virus infection in the gastrointestinal tract and central nervous system. These phenotypes were due to type 2 immune skewing, as coinfection in Stat6-/- mice rescued mortality, and treatment of WNV-infected helminth-free mice with IL-4 antibody complexes mirrors coinfection. Unexpectedly, IL-4 receptor signaling in intestinal epithelial cells mediated the susceptibility and gut phenotypes. Indeed, tuft cell-deficient mice showed improved outcomes with coinfection, whereas treatment with tuft cell-derived cytokine IL-25 or ligand succinate exacerbated disease. Helminth activation of a tuft cell-IL-4-receptor circuit in the gut detrimentally affects coinfection with a neurotropic flavivirus.