Severe COVID-19 versus multisystem inflammatory syndrome:comparing two critical outcomes of SARS-CoV-2 infection

peer reviewedSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with diverse host response immunodynamics and variable inflammatory manifestations. Several immune-modulating risk factors can contribute to a more severe coronavirus disease 2019 (COVID-19) course with increased morbidity and mortality. The comparatively rare post-infectious multisystem inflammatory syndrome (MIS) can develop in formerly healthy individuals, with accelerated progression to life-threatening illness. A common trajectory of immune dysregulation forms a continuum of the COVID-19 spectrum and MIS; however, severity of COVID-19 or the development of MIS is dependent on distinct aetiological factors that produce variable host inflammatory responses to infection with different spatiotemporal manifestations, a comprehensive understanding of which is necessary to set better targeted therapeutic and preventative strategies for both

Distinct expression profiles of TGF-β1 signaling mediators in pathogenic SIVmac and non-pathogenic SIVagm infections

BACKGROUND: The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-β1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-β1 induction persists during primary infection [1]. We raised the hypothesis that MACs are unable to respond to TGF-β1 and thus cannot resorb virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory markers as well as of factors involved in the TGF-β1 signaling pathway in SIV-infected AGMs and MACs. METHODS: Levels of transcripts encoding for pro- and anti-inflammatory markers (tnf-α, ifn-γ, il-10, t-bet, gata-3) as well as for TGF-β1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs. RESULTS: During primary SIVmac infection, up-regulations of tnf-α, ifn-γ and t-bet responses (days 1–16 p.i.) were stronger whereas il-10 response was delayed (4(th )week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 3–8 p.i.), a cellular mediator inhibiting the TGF-β1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of gata-3 but not t-bet, a longer lasting up-regulation of smad4 (days 1–21 p.i), a mediator enhancing TGF-β1 signaling, and no smad7 up-regulations. CONCLUSION: Our data suggest that the inability to resorb virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is associated with an unresponsiveness to TGF-β1

Inflammatory control in AIDS-resistant non human primates

International audienceAfrican non human primates are natural hosts of SIV. The infection is non-pathogenic despite plasma viral load levels similar to those in HIV-1 infected humans and SIVmac-infected macaques (MAC) progressing towards AIDS. The most striking difference between non-pathogenic SIV and pathogenic HIV-1/SIVmac infections is the lack of chronic T cell activation in natural hosts. In HIV and SIVmac infections, chronic T cell activation is known to drive CD4+T cell depletion. Intense research efforts are worldwide put on the search of the mechanisms that can control chronic T cell activation in HIV/SIV infections. Innate immune responses play a determinant role in the regulation of T cell activation profiles. Type I interferons (IFN-I) are part of the first-wave response of the innate immune system in viral infections. We compared the IFN-I responses between pathogenic (MAC) and non-pathogenic SIV infections (African Green monkey, AGM) at the level of blood and lymph nodes (LN) during the early and chronic stage of infection. During the acute SIVagm infection, we detected high amounts of IFN-α in the plasma of AGMs, although the mean levels at the peak were three times lower than in MAC. The microarray data revealed a rapid and strong up-regulation of type I Interferon-Stimulated Genes (ISG) in AGMs during acute SIVagm infection. ISGs denote the in vivo activity of IFN-I. Using a functional assay, we demonstrated that low IFN-α concentrations (50 times lower than the IFN-α levels in plasma at the peak) were sufficient to induce strong ISG responses in AGM and MAC cells. Surprisingly, our direct comparison of blood and LNs showed that ISG induction was broader in blood of AGMs than in MAC, while in LN, it was the contrary. Thus, in AGMs, less ISG were induced in LNs as compared to MAC already during the acute phase of infection. Moreover, our tight kinetic analysis showed that this ISG expression was efficiently controlled after day 28 post-infection in AGMs, while in MAC the ISGs expression remained uncontrolled. Finally, we identified genes that were differentially expressed between the two species and which might be involved in the discriminating responses. Altogether, this shows that AGMs are capable to mount a well coordinated and efficient regulative response to innate immune activation

Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection.

International audienceHuman immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4(+) T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV in vivo identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor. The ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing

Mdscs in Infectious diseases: regulation, roles, and readjustment

Many pathogens, ranging from viruses to multicellular parasites, promote expansion of MDSCs, which are myeloid cells that exhibit immunosuppressive features. The roles of MDSCs in infection depend on the class and virulence mechanisms of the pathogen, the stage of the disease, and the pathology associated with the infection. This work compiles evidence supported by functional assays on the roles of different subsets of MDSCs in acute and chronic infections, including pathogen-associated malignancies, and discusses strategies to modulate MDSC dynamics to benefit the host

Extremely low viral reservoir in treated chronically HIV-1-infected individuals

Altres ajuts: This research was sponsored in part by Grifols and by Merck Sharp & Dohme España, S.A. (IISP 54925). The funding organizations had no input in the design of the study; in the collection, analyses, or interpretation of the data; writing of the manuscript; or in the decision to submit the study for publication. NH received a post-doctoral grant from the Jaqueline Beytout Foundation. FG received the support of "José María Segovia de Arana" contracts (2019) and MMT from the NIH (R01AI143457).Small viral reservoirs are found predominantly in HIV-1 controllers and individuals treated during acute/early HIV-1 infection. However, other HIV + individuals could naturally also harbour low viral reservoirs. We screened 451 HIV-1-infected treated-individuals with suppressed plasma viremia for at least 3 years and stored cryopreserved peripheral blood mononuclear cells (PBMCs). Total HIV-DNA was analysed in PBMCs with ddPCR. Individuals with 50 HIV-DNA copies/10 6 PBMCs) to analyse total HIV-DNA, T-cell and NK-cell populations, HIV-1 specific antibodies, and plasma inflammation markers. We found that 9.3% of the individuals screened had <50 HIV-DNA copies/10 6 PBMCs. At least 66% initiated cART during the chronic phase of HIV-1 infection (cp-LoViReT). Cp-LoViReT harboured lower levels of HIV-DNA before cART and after treatment introduction the decays were greater compared to controls. They displayed a marked decline in quantity and avidity in HIV-specific antibodies after initiation of cART. Cp-LoViReT had fewer CD8 + T and T in the absence of cART, and higher CD8 + T after 18 months on therapy. Treated chronically HIV-1-infected LoViReT represent a new phenotype of individuals characterized by an intrinsically reduced viral reservoir, less impaired CD8 + T-cell compartment before cART, and low circulating HIV-1 antigens despite being treated in the chronic phase of infection. The identification of this unique group of individuals is of great interest for the design of future eradication studies. MSD Spai

Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection

International audienceTwo of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathway

Publisher Correction: Ancient hybridization and strong adaptation to viruses across African vervet monkey populations.

In the version of this article published, in the Online Methods eight citations to supplementary material refer to the wrong supplementary items. See the correction notice for full details

Ancient hybridization and strong adaptation to viruses across African vervet monkey populations.

Vervet monkeys are among the most widely distributed nonhuman primates, show considerable phenotypic diversity, and have long been an important biomedical model for a variety of human diseases and in vaccine research. Using whole-genome sequencing data from 163 vervets sampled from across Africa and the Caribbean, we find high diversity within and between taxa and clear evidence that taxonomic divergence was reticulate rather than following a simple branching pattern. A scan for diversifying selection across taxa identifies strong and highly polygenic selection signals affecting viral processes. Furthermore, selection scores are elevated in genes whose human orthologs interact with HIV and in genes that show a response to experimental simian immunodeficiency virus (SIV) infection in vervet monkeys but not in rhesus macaques, suggesting that part of the signal reflects taxon-specific adaptation to SIV