Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation

Osborne, Lisa C.; Monticelli, Laurel A.; Nice, Timothy J.; Sutherland, Tara E.; Siracusa, Mark C.; Hepworth, Matthew R.; Tomov, Vesselin; Kobuley, Dmytro; Tran, Sara V.; Bittinger, Kyle; Bailey, Aubrey; Laughlin, Alice; Boucher, Jean‐Luc; Wherry, E. John; Bushman, Frederic D.; Allen, Judith E.; Virgin, Herbert W.; Artis, David

doi:10.1126/science.1256942

Cited by 247 publications

(255 citation statements)

References 55 publications

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“…(iii) It is possible that the use of different substrains of C57BL/6 WT mice or different animal housing conditions in our study and that of Tahiliani et al could have altered the susceptibility of pDC-depleted mice. It is known that the endogenous microbiota differ widely between animal facilities and can significantly alter the protective immune response to virus infection (62)(63)(64). Therefore, it may not be possible to completely replicate the conditions used in the Tahiliani et al publication.…”

Section: Discussionmentioning

confidence: 95%

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Kaminsky

Sei

Parekh

et al. 2015

J Virol

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Viruses that spread systemically from a peripheral site of infection cause morbidity and mortality in the human population. Innate myeloid cells, including monocytes, macrophages, monocyte-derived dendritic cells (mo-DC), and dendritic cells (DC), respond early during viral infection to control viral replication, reducing virus spread from the peripheral site. Ectromelia virus (ECTV), an orthopoxvirus that naturally infects the mouse, spreads systemically from the peripheral site of infection and results in death of susceptible mice. While phagocytic cells have a requisite role in the response to ECTV, the requirement for individual myeloid cell populations during acute immune responses to peripheral viral infection is unclear. In this study, a variety of myeloid-specific depletion methods were used to dissect the roles of individual myeloid cell subsets in the survival of ECTV infection. We showed that DC are the primary producers of type I interferons (T1-IFN), requisite cytokines for survival, following ECTV infection. DC, but not macrophages, monocytes, or granulocytes, were required for control of the virus and survival of mice following ECTV infection. Depletion of either plasmacytoid DC (pDC) alone or the lymphoid-resident DC subset (CD8␣ ؉ DC) alone did not confer lethal susceptibility to ECTV. However, the function of at least one of the pDC or CD8␣ ؉ DC subsets is required for survival of ECTV infection, as mice depleted of both populations were susceptible to ECTV challenge. The presence of at least one of these DC subsets is sufficient for cytokine production that reduces ECTV replication and virus spread, facilitating survival following infection. IMPORTANCEPrior to the eradication of variola virus, the orthopoxvirus that causes smallpox, one-third of infected people succumbed to the disease. Following successful eradication of smallpox, vaccination rates with the smallpox vaccine have significantly dropped. There is now an increasing incidence of zoonotic orthopoxvirus infections for which there are no effective treatments. Moreover, the safety of the smallpox vaccine is of great concern, as complications may arise, resulting in morbidity. Like many viruses that cause significant human diseases, orthopoxviruses spread from a peripheral site of infection to become systemic. This study elucidates the early requirement for innate immune cells in controlling a peripheral infection with ECTV, the causative agent of mousepox. We report that there is redundancy in the function of two innate immune cell subsets in controlling virus spread early during infection. The viral control mediated by these cell subsets presents a potential target for therapies and rational vaccine design. P rior to the induction of the adaptive immune response, cells of the innate immune system are deployed early during viral infection to control the pathogen and limit its spread from the site of infection. Effector cells of the innate immune system include myeloid cell subsets: granulocytes (neutrophils, eosinophils, and b...

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Section: Discussionmentioning

confidence: 95%

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Kaminsky

Sei

Parekh

et al. 2015

J Virol

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“…viral load, damage and immune activation) and can be modified potentially by additional factors known to modify immune response, such as genetics [38], immunocompetence [39], previous exposure to similar strains [40], physiological factors (e.g. comorbidities, microbiome) [41] or co-infection [42]. Future research should consider these hypotheses when investigating the causes of symptomatic NoV infection and the role of vaccines in preventing symptoms.…”

Section: Discussionmentioning

confidence: 99%

Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding

Newman

Moe

Kirby

et al. 2016

Clinical and Experimental Immunology

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Summary Noroviruses (NoV) are the most common cause of epidemic gastroenteritis world-wide. NoV infections are often asymptomatic, although individuals still shed large amounts of NoV in their stool. Understanding the differences between asymptomatic and symptomatic individuals would help in elucidating mechanisms of NoV pathogenesis. Our goal was to compare the serum cytokine responses and faecal viral RNA titres of asymptomatic and symptomatic NoV-infected individuals. We tested serum samples from infected subjects (n = 26; 19 symptomatic, seven asymptomatic) from two human challenge studies of GI.1 NoV for 16 cytokines. Samples from prechallenge and days 1-4 post-challenge were tested for these cytokines. Cytokine levels were compared to stool NoV RNA titres quantified previously by reverse transcription–polymerase chain reaction (RT–qPCR). While both symptomatic and asymptomatic groups had similar patterns of cytokine responses, the symptomatic group generally exhibited a greater elevation of T helper type 1 (Th1) and Th2 cytokines and IL-8 post-challenge compared to the asymptomatic group (all P < 0·01). Daily viral RNA titre was associated positively with daily IL-6 concentration and negatively with daily IL-12p40 concentration (all P < 0·05). Symptoms were not associated significantly with daily viral RNA titre, duration of viral shedding or cumulative shedding. Symptomatic individuals, compared to asymptomatic, have greater immune system activation, as measured by serum cytokines, but they do not have greater viral burden, as measured by titre and shedding, suggesting that symptoms may be immune-mediated in NoV infection.

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“…First, our work implicates changes in the genital mucosa of women with schistosome infections as the likely reason that women, but not men, who have schistosome infections have an increased odds of HIV infection. Second, it implies that, if the impaired antiviral control that is induced by schistosomiasis in animals [21][22][23] leads to interactions with HIV, these parasite-virus interactions may occur after HIV infection has been acquired rather at the time of HIV exposure.…”

Section: Discussionmentioning

confidence: 99%

Schistosomiasis and Human Immunodeficiency Virus in Men in Tanzania

Downs

Dood

Dee

et al. 2017

The American Society of Tropical Medicine and Hygiene

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Abstract. Schistosomiasis is a parasitic worm infection that affects over 260 million individuals worldwide. Women with schistosome infections have been demonstrated to have a 4-fold increase in the odds of human immunodeficiency virus (HIV) infection compared with women without schistosome infections. A relationship between schistosome and HIV infections has not been clearly defined in men. Among 674 men aged 18-50 years living in rural Tanzania, we identified 429 (63.6%) who had a schistosome infection as defined by serum positivity for schistosome circulating anodic antigen, visualization of parasite eggs in urine or stool, or both. HIV infection was identified in 38 (5.6%). The odds of HIV infection was 1.3 [95% confidence interval = 0.6-2.5] (P = 0.53) among men with any schistosome infection (Schistosoma haematobium or Schistosoma mansoni), and it was 1.4 [0.6-3.3] (P = 0.43) among men with S. haematobium infection. Men with S. haematobium infection were significantly more likely to report the symptom of hemospermia than men without S. haematobium infection. We conclude that schistosome infections appear to have little to no association with HIV infection in men.

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Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation

Cited by 247 publications

References 55 publications

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection

Norovirus in symptomatic and asymptomatic individuals: cytokines and viral shedding

Schistosomiasis and Human Immunodeficiency Virus in Men in Tanzania

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