Viral infections have variable outcomes with severe disease occurring in only few individuals. We hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. To test this, mice were infected initially with IAV and in memory-phase challenged with LCMV, which we show here to have relatively minor cross-reactivity with IAV. The outcome in genetically identical mice varied from mild pneumonitis to severe acute lung injury with extensive pneumonia and bronchiolization, similar to that observed in patients that died of the 1918 H1N1 pandemic. Lesion expression did not correlate with virus titers. Instead, disease severity directly correlated with and was predicted by the frequency of IAV-PB1703- and -PA224-specific responses, which crossreacted with LCMV-GP34 and -GP276, respectively. Eradication or functional ablation of these pathogenic memory T-cell populations, using mutant-viral strains, peptide-based tolerization strategies, or short-term anti-IFNγ treatment inhibited severe lesions such as bronchiolization from occurring. Heterologous immunity can shape outcome of infections and likely individual responses to vaccination, and can be manipulated to treat or prevent severe pathology.

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© Ferrata Storti FoundationThe host systemic iron availability is controlled by the iron regulatory hormone hepcidin, 18-20 which could therefore influence the susceptibility to malaria. Iron is absorbed from the diet by intestinal enterocytes and recycled from senescent or damaged RBCs by macrophages. 21

In malaria, CD4 Th1 and T follicular helper (TFH) cells are important for controlling parasite growth, but Th1 cells also contribute to immunopathology. Moreover, various regulatory CD4 T‐cell subsets are critical to hamper pathology. Yet the antigen‐presenting cells controlling Th functionality, as well as the antigens recognized by CD4 T cells, are largely unknown. Here, we characterize the MHC II immunopeptidome presented by DC during blood‐stage malaria in mice. We establish the immunodominance hierarchy of 14 MHC II ligands derived from conserved parasite proteins. Immunodominance is shaped differently whether blood stage is preceded or not by liver stage, but the same ETRAMP‐specific dominant response develops in both contexts. In naïve mice and at the onset of cerebral malaria, CD8α+ dendritic cells (cDC1) are superior to other DC subsets for MHC II presentation of the ETRAMP epitope. Using in vivo depletion of cDC1, we show that cDC1 promote parasite‐specific Th1 cells and inhibit the development of IL‐10+ CD4 T cells. This work profiles the P. berghei blood‐stage MHC II immunopeptidome, highlights the potency of cDC1 to present malaria antigens on MHC II, and reveals a major role for cDC1 in regulating malaria‐specific CD4 T‐cell responses.

Prior immunity to influenza A virus (IAV) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (LCMV)infection During a lifetime the immune system is shaped by a history of infections. Prior infections with one pathogen may influence the severity of disease outcome to a subsequent infection with an unrelated pathogen, a phenomenon known as heterologous immunity (1). Enhanced immunopathology, which can be mediated by the activation of cross-reactive memory T cells, is one of the harmful consequences of heterologous immunity. For instance, it has been proposed during human infections that cross-reactive IAV-specific memory CD8 ϩ T cells can contribute to the induction of severe fulminant hepatitis during hepatitis C virus (HCV) infection and induction of acute infectious mononucleosis during Epstein-Barr virus (EBV) infection (2-4).Lung pathology is a common manifestation of respiratory infections and can vary greatly in severity in different individuals infected with the same pathogen. To investigate the role of altered immunopathology during heterologous immunity in a controlled experimental setting, we utilized a mouse model of IAV-immune mice infected with lymphocytic choriomeningitis virus (LCMV) (5). We initially chose these two viruses because they are phylogenetically unrelated and because they are naturally spread through infection of the respiratory mucosa and induce significant inflammation in the lung (6-11). Influenza virus is an extremely common respiratory pathogen in humans, and LCMV, which induces a flu-like illness in humans, is also a relatively common pathogen, with 5 to 14% of the general population being serologically positive (12). These IAV-immune mice infected with LCMV could develop acute lung injury similar to that seen in individuals that died during the H1N1 IAV pandemic in 1918, with enhanced bronchus-associated lymphoid tissue (BALT), mononuclear pneumonia, necrotizing bronchiolitis, vasculitis, and bronchiolization (13, 14) The severity of lung pathology varied among genetically identical mice from mild pneumonitis to severe mononuclear pneumonia, necrotizing bronchiolitis, and bronchiolization, an abnormal alveolar epithelial repair process considered premalignant and associated with idiopathic pulmonary fibrosis in humans. Although counterintuitive, severity of pathology did not directly correlate with LCMV titers. Instead, increased pathology was dependent on cross-reactive IAV-specific memory CD8 ϩ T cells (15). Disease severity was directly correlated with and could be predicted by the frequency of two IAV epitope-specific CD8 ϩ T-cell populations, PB1 703 and PA 224 , which are crossreactive with LCMV-GP 34 and -GP 276 , respectively. Eradication or functional ablation of these pathogenic populations of IAV-specific memory T cells using mutant viral strains, peptide-based tolerization strategies, or short-term anti-gamma interferon (IFN-␥) treatment prevented this pathology.Here, we continue to investigate this mouse model to determine if there are ot...

To evaluate the impact of immunodominance on CD8 T-cell properties, we compared the functional properties of dominant and subdominant populations in the response to lymphocytic choriomeningitis virus (LCMV). To improve functional discrimination, in addition to the usual tests of phenotype and function, we used a sensitive technique that allows the screening of all CD8 effector genes simultaneously in single cells. Surprisingly, these methods failed to reveal a major impact of clonal dominance in CD8 properties throughout the response. Aiming to increase clonal dominance, we examined high-frequency transferred P14 T-cell receptor transgenic (TCR Tg) cells. Under these conditions LCMV is cleared faster, and accordingly we found an accelerated response. However, when Tg and endogenous cells were studied in the same mice, where they should be subjected to the same antigen load, they showed overlapping properties, and the presence of P14 cells did not modify endogenous responses to other LCMV epitopes or a perturbed immunodominance hierarchy in the memory phase. Using allotype-labeled Tg cells, we found that during acute infection up to 80% downregulated their TCR and were undetectable by tetramer binding, and that tetramer-negative and tetramer-positive cells had very different features. Since Tg cells are not available to evaluate immune responses in humans and, in many cases, are not available from the mouse, the tetramer-based evaluation of early immune responses in most situations of high viremia may be incomplete and biased.

Coinfections shape immunity and influence the development of inflammatory diseases, resulting in detrimental or beneficial outcome. Coinfections with concurrent Plasmodium species can alter malaria clinical evolution, and malaria infection itself can modulate autoimmune reactions. Yet, the underlying mechanisms remain ill defined. Here, we demonstrate that the protective effects of some rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus cohosted in malaria-parasitized blood. We show that live and extracts of blood parasitized by Plasmodium berghei K173 or Plasmodium yoelii 17X YM, protect against P. berghei ANKA-induced experimental cerebral malaria (ECM) and myelin oligodendrocyte glycoprotein (MOG)/complete Freund’s adjuvant (CFA)-induced experimental autoimmune encephalomyelitis (EAE), and that protection is associated with a strong type I interferon (IFN-I) signature. We detected the presence of the RNA virus lactate dehydrogenase-elevating virus (LDV) in the protective Plasmodium stabilates and we established that LDV infection alone was necessary and sufficient to recapitulate the protective effects on ECM and EAE. In ECM, protection resulted from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and impairment of their ability to produce interleukin (IL)-12p70, leading to a decrease in pathogenic CD4+ Th1 responses. In EAE, LDV infection induced IFN-I-mediated abrogation of IL-23, thereby preventing the differentiation of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing encephalitogenic CD4+ T cells. Our work identifies a virus cohosted in several Plasmodium stabilates across the community and deciphers its major consequences on the host immune system. More generally, our data emphasize the importance of considering contemporaneous infections for the understanding of malaria-associated and autoimmune diseases. IMPORTANCE Any infection modifies the host immune status, potentially ameliorating or aggravating the pathophysiology of a simultaneous inflammatory condition. In the course of investigating how malaria infection modulates the severity of contemporaneous inflammatory diseases, we identified a nonpathogenic mouse virus in stabilates of two widely used rodent parasite lines: Plasmodium berghei K173 and Plasmodium yoelii 17X YM. We established that the protective effects of these Plasmodium lines on cerebral malaria and multiple sclerosis are exclusively due to this virus. The virus induces a massive type I interferon (IFN-I) response and causes quantitative and qualitative defects in the ability of dendritic cells to promote pathogenic T cell responses. Beyond revealing a possible confounding factor in rodent malaria models, our work uncovers some bases by which a seemingly innocuous viral (co)infection profoundly changes the immunopathophysiology of inflammatory diseases.

AbstractCo-infections shape the host immune status, thereby influencing the development of inflammatory diseases, which can result in detrimental or beneficial effects. For example, co-infections with concurrent Plasmodium species can alter malaria clinical evolution and malaria infection itself has the ability to modulate autoimmune reactions but, in both cases, the underlying mechanisms remain ill-defined.Here, we demonstrate that the protective effects of certain rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus co-hosted in malaria-parasitized blood. We show that live as well as extracts of blood parasitized by P. berghei K173 or P. yoelii 17X YM, confer full protection against Pb ANKA (PbA)-induced Experimental Cerebral Malaria (ECM) and MOG/CFA-induced experimental autoimmune encephalomyelitis (EAE), and that this is associated with a strong type I IFN signature. We detected the presence of a viral element, the RNA virus Lactate Dehydrogenase-elevating Virus (LDV), in the protective Plasmodium stabilates and we established that infection with LDV alone recapitulates the protective effects on ECM and EAE. In ECM, we further show that protection results from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and in their ability to produce the Th1-inducing IL-12p70, leading to a decrease in pathogenic CD4+ Th1 responses. In EAE, protection is achieved by IFN-I mediated blunting of IL-12 and IL-23, preventing the differentiation of IFN-γ-, IL-17- and GM-CSF-producing encephalitogenic CD4+ T cells.Thus, our results identify a virus that is co-hosted in several Plasmodium stabilates across the community and has major consequences on the host immune system. Moreover, our data emphasize the importance of considering concurrent infections for the understanding of autoimmunity and malaria-associated inflammatory complications.