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Chikungunya virus (CHIKV) and Ross River virus (RRV) are mosquito-transmitted alphaviruses that cause debilitating acute and chronic musculoskeletal disease. Monocytes are implicated in the pathogenesis of these infections; however, their specific roles are not well defined. To investigate the role of inflammatory Ly6ChiCCR2+ monocytes in alphavirus pathogenesis, we used CCR2-DTR transgenic mice, enabling depletion of these cells by administration of diptheria toxin (DT). DT-treated CCR2-DTR mice displayed more severe disease following CHIKV and RRV infection and had fewer Ly6Chi monocytes and NK cells in circulation and muscle tissue compared with DT-treated WT mice. Furthermore, depletion of CCR2+ or Gr1+ cells, but not NK cells or neutrophils alone, restored virulence and increased viral loads in mice infected with an RRV strain encoding attenuating mutations in nsP1 to levels detected in monocyte-depleted mice infected with fully virulent RRV. Disease severity and viral loads also were increased in DT-treated CCR2-DTR+;Rag1-/- mice infected with the nsP1 mutant virus, confirming that these effects are independent of adaptive immunity. Monocytes and macrophages sorted from muscle tissue of RRV-infected mice were viral RNA positive and had elevated expression of Irf7, and co-culture of Ly6Chi monocytes with RRV-infected cells resulted in induction of type I IFN gene expression in monocytes that was Irf3;Irf7 and Mavs-dependent. Consistent with these data, viral loads of the attenuated nsP1 mutant virus were equivalent to those of WT RRV in Mavs-/- mice. Finally, reconstitution of Irf3-/-;Irf7-/- mice with CCR2-DTR bone marrow rescued mice from severe infection, and this effect was reversed by depletion of CCR2+ cells, indicating that CCR2+ hematopoietic cells are capable of inducing an antiviral response. Collectively, these data suggest that MAVS-dependent production of type I IFN by monocytes is critical for control of acute alphavirus infection and that determinants in nsP1, the viral RNA capping protein, counteract this response.

Natural killer (NK) cells are important innate effector cells that are well described in their ability to kill virally-infected cells and tumors. However, there is increasing appreciation for the role of NK cells in the control of other pathogens, including intracellular parasites such as Plasmodium , the cause of malaria. NK cells may be beneficial during the early phase of Plasmodium infection—prior to the activation and expansion of antigen-specific T cells—through cooperation with myeloid cells to produce inflammatory cytokines like IFNγ. Recent work has defined how Plasmodium can activate NK cells to respond with natural cytotoxicity, and inhibit the growth of parasites via antibody-dependent cellular cytotoxicity mechanisms (ADCC). A specialized subset of adaptive NK cells that are negative for the Fc receptor γ chain have enhanced ADCC function and correlate with protection from malaria. Additionally, production of the regulatory cytokine IL-10 by NK cells prevents overt pathology and death during experimental cerebral malaria. Now that conditional NK cell mouse models have been developed, previous studies need to be reevaluated in the context of what is now known about other immune populations with similarity to NK cells (i.e., NKT cells and type I innate lymphoid cells). This brief review summarizes recent findings which support the potentially beneficial roles of NK cells during Plasmodium infection in mice and humans. Also highlighted are how the actions of NK cells can be explored using new experimental strategies, and the potential to harness NK cell function in vaccination regimens.

WHEN AN ANTIVIRAL IMMUNE RESPONSE IS GENERATED, A BALANCE MUST BE REACHED BETWEEN TWO OPPOSING PATHWAYS: the production of proinflammatory and cytotoxic effectors that drive a robust antiviral immune response to control the infection and regulators that function to limit or blunt an excessive immune response to minimize immune-mediated pathology and repair tissue damage. Myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activities of the arginine-hydrolyzing enzymes nitric oxide synthase 2 (Nos2; iNOS) and arginase 1 (Arg1). Nitric oxide (NO) production by iNOS is an important proinflammatory mediator, whereas Arg1-expressing macrophages contribute to the resolution of inflammation and wound repair. In the context of viral infections, expression of these enzymes can result in a variety of outcomes for the host. NO has direct antiviral properties against some viruses, whereas during other virus infections NO can mediate immunopathology and/or inhibit the antiviral immune response to promote chronic infection. Arg1 activity not only has important wound healing functions but can also inhibit the antiviral immune response during some viral infections. Thus, depending on the specific virus and the tissue(s) involved, the activity of both of these arginine-hydrolyzing enzymes can either exacerbate or limit the severity of virus-induced disease. In this review, we will discuss a variety of viral infections, including HIV, SARS-CoV, LCMV, HCV, RSV, and others, where myeloid cells influence the control and clearance of the virus from the host, as well as the severity and resolution of tissue damage, via the activities of iNOS and/or Arg1. Clearly, monocyte/macrophage activation and arginine metabolism will continue to be important areas of investigation in the context of viral infections.

Natural killer (NK) cells can produce IFNγ or IL-10 to regulate inflammation and immune responses but the factors driving NK cell IL-10 secretion are poorly-defined. Here, we identified NK cell-intrinsic STAT3 activation as vital for IL-10 production during both systemic (Lm) infection and following IL-15 cytokine/receptor complex (IL15C) treatment for experimental cerebral malaria (ECM). In both contexts, conditional deficiency in NK cells abrogated production of IL-10. Initial NK cell STAT3 phosphorylation was driven by IL-15. During Lm infection, this required capture or presentation of IL-15 by NK cell IL-15Rα. Persistent STAT3 activation was required to drive measurable IL-10 secretion and required NK cell expression of IL-10Rα. Survival-promoting effects of IL-15C treatment in ECM were dependent on NK cell while NK cell-intrinsic deficiency for , or abrogated NK cell IL-10 production and increased resistance against Lm. NK cell deficiency did not impact production of IFNγ, indicating the STAT3 activation initiated by IL-15 and amplified by IL-10 selectively drives the production of anti-inflammatory IL-10 by responding NK cells.

Although CD4 T cell memory is a critical component of adaptive immunity, antigen-specific CD4 T cell recall responses to secondary infection have been inadequately studied. Here we examine the kinetics of the secondary response in an important immunological model, infection with attenuated (Lm). We identify CD4 T cell subsets that preferentially expand during a secondary response and highlight the importance of prime-boost strategies in expanding and maintaining antigen-specific, tissue-resident memory CD4 T cells. Following intravenous infection with an attenuated strain of Lm, we found that total antigen-specific CD4 T cells responded more robustly in secondary compared with primary infection, reaching near-peak levels in secondary lymphoid organs (SLOs) and the liver by three days post-infection. During the secondary response, CD4 T cells also contracted more quickly. Primary Lm infection generated two main classes of effector cells: Th1 cells that assist macrophages and T follicular helper (Tfh) cells that aid B cells in antibody production. We found that during the secondary response, a population of Ly6C Tfh cells emerged in SLOs and was the basis for the skewing of this response to a Tfh phenotype. Deletion of T-bet in T cells precluded development of Ly6C Tfh cells, but did not alter anti-Lm antibody responses. Moreover, during recall responses, CD49a Th1 cells preferentially expanded and accumulated in the liver, achieving a new set point. Parabiosis experiments indicated that, in contrast to Tfh cells and most splenic Th1 cells, the majority of CD49a Th1 cells in the liver were tissue resident. Overall, these data demonstrate a robust secondary CD4 T cell response that differs in kinetics and composition from the primary response and provide insight into targets to enhance both peripheral and tissue-resident CD4 T cell responses.

Self-specific CD8 + T cells can escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8 + T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking this enzyme (due to deficiency in Dct , which encodes Trp2). Phenotypic and gene expression profiles of pre-immune Trp2/K b -specific cells were similar; the size of this population was only slightly reduced in wild-type (WT) compared to Dct -deficient ( Dct -/- ) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/K b -specific cells showed blunted expansion and less readily differentiated into a CD25 + proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/K b -specific cells mediated vitiligo much less efficiently. Hence, CD8 + T cell self-specificity is poorly predicted by precursor frequency, phenotype, or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.

Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus (CHIKV), are responsible for explosive epidemics involving millions of cases. These mosquito-transmitted viruses cause inflammation and injury in skeletal muscle and joint tissues that results in debilitating pain. We previously showed that arginase 1 (Arg1) was highly expressed in myeloid cells in the infected and inflamed musculoskeletal tissues of RRV- and CHIKV-infected mice, and specific deletion of Arg1 from myeloid cells resulted in enhanced viral control. Here, we show that Arg1, along with other genes associated with suppressive myeloid cells, is induced in PBMCs isolated from CHIKV-infected patients during the acute phase as well as the chronic phase, and that high Arg1 expression levels were associated with high viral loads and disease severity. Depletion of both CD4 and CD8 T cells from RRV-infected Arg1-deficient mice restored viral loads to levels detected in T cell-depleted wild-type mice. Moreover, Arg1-expressing myeloid cells inhibited virus-specific T cells in the inflamed and infected musculoskeletal tissues, but not lymphoid tissues, following RRV infection in mice, including suppression of interferon-γ and CD69 expression. Collectively, these data enhance our understanding of the immune response following arthritogenic alphavirus infection and suggest that immunosuppressive myeloid cells may contribute to the duration or severity of these debilitating infections.

P.falciparum infection can trigger high levels of inflammation that lead to fever and sometimes severe disease. People living in malaria-endemic areas gradually develop resistance to symptomatic malaria and control both parasite numbers and the inflammatory response. We previously found that adaptive NK cells correlated with reduced parasite load and protection from symptoms. We also found that murine NK cell production of IL-10 protected mice from experimental cerebral malaria. Human NK cells can also secrete IL-10, but it is unknown what NK cell subsets produce IL-10 or if this is affected by malaria experience. We hypothesized that NK cell immunoregulation may lower inflammation and reduce fever induction. Here, we showed that NK cells from participants with malaria experience make significantly more IL-10 than participants with no malaria experience. We then determined the proportions of NK cells that are cytotoxic and produce IFN-γ and/or IL-10 and identified a signature of adaptive and checkpoint molecules on IL-10–producing NK cells. Lastly, we found that coculture with primary monocytes, Plasmodium -infected RBCs, and antibody induced IL-10 production by NK cells. These data suggest that NK cells may contribute to protection from malaria symptoms via IL-10 production.

Abstract Background Long COVID is a common complication of infection with severe acute respiratory syndrome coronavirus 2, but the prevalence and predictors of the condition remain poorly characterized. Methods We prospectively studied adults (≥18 years) with acute coronavirus disease 2019 (COVID-19) presenting to an urban safety net hospital and associated clinics between July 2020 and December 2022. Logistic regression models were used to evaluate the association between baseline demographic, clinical, and laboratory characteristics with long COVID status, defined as symptoms persisting at least 9 months after acute disease. Among unrecovered participants, we describe the prevalence of individual symptoms. Results We enrolled 222 participants, 162 (73%) of whom had known recovery status by 9 months. Median age was 54 years, half (55%) were female, and the majority of participants (78%) had at least 1 comorbidity at the time of COVID-19 diagnosis. Based on acute illness characteristics, the adjusted odds ratio for long COVID was 3.0 (95% confidence interval [CI], 1.1–8.0) among those with detectable nucleocapsid antigen and 3.6 (95% CI, 1.2–11) for those who required supplemental oxygen. Of the 41% of participants with symptoms persisting at least 9 months, central nervous system and psychological symptoms were most commonly reported, with 57% reporting functional limitations due to their persistent symptoms. Conclusions The strong association with initial disease suggests a decreasing prevalence of long COVID as acute illnesses become milder. However, many contemporary patients still experience high viral burden with extended viral replication, even after vaccination. Our findings highlight the importance of properly characterizing long COVID as viral evolution shifts acute disease presentation.

Chikungunya virus (CHIKV), and several related alphaviruses, are mosquito-transmitted viruses that cause debilitating musculoskeletal disease in humans. Since 2004, CHIKV has caused millions of disease cases in the Indian Ocean region and has emerged in new areas, including Italy, France, the Middle East and the Pacific region [1]. [...]RRV RNA was detected in knee biopsies collected 5 weeks after the onset of joint symptoms [33].