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Hallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells.

ABSTRACT: Innate lymphoid cells (ILCs) play critical roles in mucosal barrier defense and tissue homeostasis. While ILCs are depleted in HIV-1 infection, this phenomenon is not a generalized feature of all viral infections. Here we show in untreated SIV-infected rhesus macaques (RMs) that ILC3s are lost rapidly in mesenteric lymph nodes (MLNs), yet preserved in SIV+ RMs with pharmacologic or natural control of viremia. In healthy uninfected RMs, experimental depletion of CD4+ T cells in combination with dextran sodium sulfate (DSS) is sufficient to reduce ILC frequencies in the MLN. In this setting and in chronic SIV+ RMs, IL-7R? chain expression diminishes on ILC3s in contrast to the IL-18R? chain expression which remains stable. In HIV-uninfected patients with durable CD4+ T cell deficiency (deemed idiopathic CD4+ lymphopenia), similar ILC deficiencies in blood were observed, collectively identifying determinants of ILC homeostasis in primates and potential mechanisms underlying their depletion in HIV/SIV infection.

SUBMITTER: Mudd JC

PROVIDER: S-EPMC6160474 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Hallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells.

Mudd Joseph C JC Busman-Sahay Kathleen K DiNapoli Sarah R SR Lai Stephen S Sheik Virginia V Lisco Andrea A Deleage Claire C Richardson Brian B Palesch David J DJ Paiardini Mirko M Cameron Mark M Sereti Irini I Reeves R Keith RK Estes Jacob D JD Brenchley Jason M JM

Nature communications 20180927 1

Innate lymphoid cells (ILCs) play critical roles in mucosal barrier defense and tissue homeostasis. While ILCs are depleted in HIV-1 infection, this phenomenon is not a generalized feature of all viral infections. Here we show in untreated SIV-infected rhesus macaques (RMs) that ILC3s are lost rapidly in mesenteric lymph nodes (MLNs), yet preserved in SIV<sup>+</sup> RMs with pharmacologic or natural control of viremia. In healthy uninfected RMs, experimental depletion of CD4<sup>+</sup> T cells ...[more]

PMID: 30262807

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Project description:ObjectivesInnate lymphoid cells (ILCs) share many characteristics with CD4+ T cells, and group 1 ILCs share a requirement for T-bet and the ability to produce IFNγ with T helper 1 (Th1) cells. Given this similarity, and the importance of Th1 cells for protection against intracellular protozoan parasites, we aimed to characterise the role of group 1 ILCs during Plasmodium infection.MethodsWe quantified group 1 ILCs in peripheral blood collected from subjects infected with with Plasmodium falciparum 3D7 as part of a controlled human malaria infection study, and in the liver and spleens of Pc AS-infected mice. We used genetically-modified mouse models, as well as cell-depletion methods in mice to characterise the role of group 1 ILCs during Pc AS infection.ResultsIn a controlled human malaria infection study, we found that the frequencies of circulating ILC1s and NK cells decreased as infection progressed but recovered after volunteers were treated with antiparasitic drug. A similar observation was made for liver and splenic ILC1s in P. chabaudi chabaudi AS (Pc AS)-infected mice. The decrease in mouse liver ILC1 frequencies was associated with increased apoptosis. We also identified a population of cells within the liver and spleen that expressed both ILC1 and NK cell markers, indicative of plasticity between these two cell lineages. Studies using genetic and cell-depletion approaches indicated that group 1 ILCs have a limited role in antiparasitic immunity during Pc AS infection in mice.DiscussionOur results are consistent with a previous study indicating a limited role for natural killer (NK) cells during Plasmodium chabaudi infection in mice. Additionally, a recent study reported the redundancy of ILCs in humans with competent B and T cells. Nonetheless, our results do not rule out a role for group 1 ILCs in human malaria in endemic settings given that blood stage infection was initiated intravenously in our experimental models, and thus bypassed the liver stage of infection, which may influence the immune response during the blood stage.ConclusionOur results show that ILC1s are lost early during mouse and human malaria, and this observation may help to explain the limited role for these cells in controlling blood stage infection.

Project description:BackgroundRisk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations.MethodsMultiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n = 40), treated for COVID-19 as outpatients (n = 51), and in uninfected controls (n = 86), as well as in children with COVID-19 (n = 19), recovering from COVID-19 (n = 14), MIS-C (n = 11), recovering from MIS-C (n = 7), and pediatric controls (n = 17).ResultsThis observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls.ConclusionsThese results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males.FundingThis work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183.

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Hallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells.

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Hallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells.

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