Neutrophils Mediate Immunopathology and Negatively Regulate Protective Immune Responses during Fatal Bacterial Infection-Induced Toxic Shock

Abstract

c Ehrlichia chaffeensis is an obligate intracellular bacterium that infects primarily monocytes and macrophages and causes potentially fatal human monocytic ehrlichiosis (HME) that mimics toxic-shock-like syndrome in immunocompetent hosts. Early recruitment of neutrophils to the sites of infection is critical for the control of bacterial infection and inflammatory responses. We recently observed rapid and sustained neutrophil recruitment at a primary site of infection (peritoneum) following lethal murine ehrlichial infection compared to innocuous ehrlichial infection. We examined here the contribution of neutrophils to protective immunity or immunopathology during infection with monocytic Ehrlichia. Unexpectedly, depletion of neutrophils from lethally infected mice enhanced bacterial elimination, decreased immune-mediated pathology, and prolonged survival.

Effects of Lipoxin A4 on antimicrobial actions of neutrophils in sepsis

“…Data on the changes in neutrophil phagocytic ability in sepsis is unclear, where CLP-sepsis increased neutrophil phagocytic ability [18] and other reports show that host or bacterial derived products, and/or impaired signaling can reduce neutrophil phagocytic ability [10,42]. Our data suggests that CLP sepsis did not alter blood and peritoneal neutrophil phagocytic index despite significant bacteremia.…”

“…On the other hand, delayed neutrophil apoptosis is associated with tissue injury in systemic inflammatory response syndrome (SIRS), sepsis and trauma [12][13][14][15][16]. Furthermore, in delayed neutrophil apoptosis, bacteria may evade detection while living within the cells and establish productive infectivity at a later time [17] In the specific case of Ehrlichia chaffeensis induced toxic shock, depletion of neutrophils actually reduced bacterial load [18].…”

Type I Interferon Contributes to Noncanonical Inflammasome Activation, Mediates Immunopathology, and Impairs Protective Immunity during Fatal Infection with Lipopolysaccharide-Negative Ehrlichiae

“…*P 0.05. ajp.amjpathol.org -The American Journal of Pathology Immunopathology, marked by host-cell apoptosis and hepatic microvesicular steatosis, is a major mechanism responsible for multiorgan failure during lethal ehrlichial infection in mice (Figure 9, A and B) and humans. 13,14,21,26,70 Both the correlation between the attenuation of pathology and host-cell death and the resistance to fatal ehrlichiosis in Ifnar1 À/À mice and the lack of correlation between effective bacterial elimination and survival in Nlrp3 À/À mice strongly support the conclusion that fatal ehrlichiosis is due mainly to excessive immunopathology. Activation of caspase-11 is known to trigger inflammatory host-cell death (ie, pyroptosis) 36,71,72 associated with secretion of IL-1a and IL-1b, both of which are detected in fatal ehrlichial infection (Figure 1).…”

Poorly Cross-Linked Peptidoglycan in MRSA Due to mecA Induction Activates the Inflammasome and Exacerbates Immunopathology

“…IL-1β is thought to be a critical cytokine for effective control of S. aureus skin infections (Miller et al, 2006), being particularly important for recruitment of neutrophils (Cho et al, 2012). However, increased neutrophil recruitment and activation can potentially cause immunopathology as observed in our study, so the process must be balanced carefully (Fournier and Parkos, 2012, Yang et al, 2013). …”