Neutrophil extracellular trap production contributes to pathogenesis in SIV-infected nonhuman primates

Abstract

Neutrophil extracellular traps (NETs) are involved in the pathogenesis of many infectious diseases, yet their dynamics and impact on HIV/SIV infection have not yet been assessed. We hypothesized that SIV infection and the related microbial translocation trigger NET activation and release (NETosis), and we investigated the interactions between NETs and immune cell populations and platelets. We compared and contrasted the levels of NETs between SIV-uninfected, SIV-infected, and SIV-infected antiretroviral-treated nonhuman primates. We also cocultured neutrophils from these animals with either peripheral blood mononuclear cells or platelets. Increased NET production was observed throughout SIV infection. In chronically infected animals, NETs were found in the gut, lung, and liver, and in the blood vessels of kidney and heart. Antiretroviral therapy (ART) decreased NETosis, albeit above preinfection levels. NETs captured CD4+ and CD8+ T cells, B cells, and monocytes, irrespective of their infection status, potentially contributing to the indiscriminate generalized immune cell loss characteristic to HIV/SIV infection, and limiting the CD4+ T cell recovery under ART. By capturing and facilitating aggregation of platelets, and through expression of increased tissue factor levels, NETs may also enhance HIV/SIV-related coagulopathy and promote cardiovascular comorbidities.

African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

“…Historically, it has been shown that both uninfected RMs [73] and HIV-uninfected patients [53,112] tend to have very small numbers of neutrophils resident in the gut, so their presence in AGMs suggests some role in responding to SIV infection. One possible explanation is that the resident gut neutrophils respond immediately to any possible leakage, no matter how minimal, from the gut lumen during the acute infection, through mechanisms like phagocytosis and the release of NETs [113,114]. Indeed, we did see a significant increase in the number of MPO-positive cells in the colon only during the ramp-up period, possibly indicating a transient increase of neutrophils during the earliest period following infection.…”

SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology

“…NETs are highly detected in the tracheal aspirate and lung tissue from COVID-19 patients Lung inflammation is the primary cause of life-threatening respiratory disorder in critical and severe forms of COVID-19 (Guan et al, 2020). NETs have been identified in the lung tissue of viral and nonviral infected patients and experimental animals (Sivanandham et al, 2018;Dicker et al, 2018). We next investigated the content of NETs in the tracheal aspirate obtained from patients with severe COVID-19 under mechanical ventilation admitted to the intensive care unit or in the lung sections from postmortem COVID-19.…”

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

“…In response to myriad external stimuli, neutrophils release potent enzymes such as neutrophil elastase (NE) and myeloperoxidase (MPO) from cytoplasmic granules (Borregaard et al, 2007). Although neutrophils contribute to host immunity, excessive recruitment of neutrophils and their release of granule components along with nuclear chromatin, or neutrophil extracellular traps (NETs), (Brinkmann et al, 2004) aggravate tissue injury and may lead to death in several disease conditions (Xu et al, 2009;Abrams et al, 2013;Sivanandham et al, 2018). NETs lead to a dispersal of toxic molecules: histones and granule proteins such as MPO, NE, and proteinase 3 (Narasaraju et al, 2011;Ashar et al, 2018;Zhu et al, 2018), and, importantly, NETs strongly stimulate the production of pro-inflammatory cytokines (Muller and Radic, 2016).…”