Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing

Abstract

The intestinal barrier, one of the first targets of HIV/simian immunodeficiency virus (SIV) is subjected to major physiological changes during acute infection. Having previously shown that pharmaceutical injection of interleukin-7 (IL-7) triggers chemokine expression in many organs leading to massive T-cell homing, in particular to the intestine, we here explored mucosal IL-7 expression as part of the cytokine storm occurring during the acute phase of SIV infection in rhesus macaques. Quantifying both mRNA and protein in tissues, we demonstrated a transient increase of IL-7 expression in the small intestine of SIV-infected rhesus macaques, starting with local detection of the virus by day 3 of infection. We also observed increased transcription levels of several chemokines in the small intestine. In infected macaques, ileal IL-7 expression correlated with the transcription of four of these chemokines. Among these chemokines, the macrophage and/or T-cell attractant chemokines CCL4, CCL25, and CCL28 also demonstrated increased transcription in uninfected IL-7-treated monkeys. Through immunohistofluorescence staining and image analysis, we observed increased CD8+ T-cell numbers and stable CD4+ T-cell counts in the infected lamina propria (LP) during hyperacute infection. Concomitantly, circulating CCR9+beta7+ CD4+ and CD8+ T-cells dropped during acute infection, suggesting augmented intestinal homing of gut-imprinted T-cells. Finally, CD4+ macrophages transiently decreased in the submucosa and concentrated in the LP during the first days of infection. Overall, our study identifies IL-7 as a danger signal in the small intestine of Chinese rhesus macaques in response to acute SIV infection. Through stimulation of local chemokine expressions, this overexpression of IL-7 triggers immune cell recruitment to the gut. These findings suggest a role for IL-7 in the initiation of early mucosal immune responses to SIV and HIV infections. However, IL-7 triggered CD4+ T-cells and macrophages localization at viral replication sites could also participate to viral spread and establishment of viral reservoirs.

Protective Reactive Thymus Hyperplasia in the COVID-19 Acute Respiratory Distress Syndrome

“…Surprisingly, contrarily to previous observations in lymphopenic patients, IL-7 plasma level was proportional to blood lymphocyte counts in COVID patients. This observation indicates that during acute SARS-Cov2 infection, high IL-7 plasma levels were not due to its low consumption by T-cells as previously suggested [28], but most probably originate from an active overproduction, as previously evidenced in acute SIV-infection in rhesus macaques [29]. Contrary to thymic production, the actual size of thymus in CT-scans of patients belonging to subgroups A and B of thymus classi cation was not inversely correlated with lymphopenia.…”

Stage-specific IFN-induced and IFN gene expression reveal convergence of type I and type II IFN and highlight their role in both acute and chronic stage of pathogenic SIV infection

“…Primary infection was characterized by a burst of expression of IFNs and IFN-induced pro-inflammatory cytokines (IL-1b, IL-6, IL-15 and IFN-γ), chemokines (CXCL9,10,11, CCL3, 8, 11, 28), and IFN-induced chemokine receptors (CCR1, CCR5, CXCR3), whereas this pattern was reduced to IFN-γ in the chronic phase, despite persistent viral replication in the PLNs. Although most of these genes are also inducible by other factors [ 70 , 71 ], most are inducible by both type I IFNs and type II IFN. This suggests that high type I IFN and type II IFN expression during primary infection synergize to take part in inflammation in lymph nodes, creating a favorable milieu for immune cell recruitment.…”

Innate Lymphoid Cells in HIV/SIV Infections

“…One potential avenue that could be explored to restore ILC and gut integrity is IL-7-based therapies. Indeed in mice, IL-7 promoted IL-22 production during chronic LCMV infection ( 108 ); and in macaques, IL-7 therapy was shown to improve gut mucosal integrity in acute SIV-infected animals ( 109 ). Similarly, IL-7 immunotherapy in chronically infected HIV patients were associated with CD4 + T cell protective functions ( 108 , 110 , 111 ) and led to an overall reduced systemic inflammation ( 110 ).…”