Neutrophil Responses toMycobacterium tuberculosisInfection in Genetically Susceptible and Resistant Mice

Abstract

The role of neutrophils in tuberculosis (TB) resistance and pathology is poorly understood. Neutrophil reactions are meant to target the offending pathogen but may lead to destruction of the host lung tissue, making the defending cells an enemy. Here, we show that mice of the I/St strain which are genetically susceptible to TB show an unusually high and prolonged neutrophil accumulation in their lungs after intratracheal infection. Compared to neutrophils from more resistant A/Sn mice, I/St neutrophils display an increased mobility and tissue influx, prolonged lifespan, low expression of the CD95 (Fas) apoptotic receptor, relative resistance to apoptosis, and an increased phagocytic capacity for mycobacteria. Segregation genetic analysis in (I/St ؋ A/Sn)F 2 hybrids indicates that the alleles of I/St origin at the chromosome 3 and 17 quantitative trait loci which are involved in the control of TB severity also determine a high level of neutrophil influx. These features, along with the poor ability of neutrophils to restrict mycobacterial growth compared to that of lung macrophages, indicate that the prevalence of neutrophils in TB inflammation contributes to the development of pathology, rather than protection of the host, and that neutrophils may play the role of a "Trojan horse" for mycobacteria.

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

“…Although the role of neutrophils in protection and pathogenesis in TB remains controversial, these effector cells clearly contribute to inflammation in acute TB [95,96]. The involvement of neutrophil-mediated lung injury could participate in the formation of necrotic and caseous granulomas [97].…”

Biomarker responses to weaning stress in beef calves

“…In the short term, the increased concentration of CXCL8 likely served to enhance neutrophil migration and surveillance of the tissues most at risk from infection. However, prolonged exposure to inflammatory cytokines can paradoxically result in deleterious effects, producing severe tissue damage, particularly in soft tissues such as the lung (Buckham-Sporer et al, 2007;Eruslanov et al, 2005;Mitchell et al, 2008) and thus increasing the susceptibility of the calves to disease. More recently, O'Loughlin et al (2011) reported that the expression of proinflammatory cytokine genes in leukocytes, including CXCL8, were upregulated up to 7 days in calves following weaning and housing.…”

Fcγ Receptors Regulate Immune Activation and Susceptibility during Mycobacterium tuberculosis Infection

“…Increased pulmonary neutrophilia is associated with enhanced susceptibility and exacerbated inflammatory pathology in mouse models of TB (3,39), and reduction in neutrophils correlates with TB treatment success in humans (40). Accordingly, we examined the levels of Ly6G ϩ , F4/80 Ϫ neutrophils in the lungs of RIIB Ϫ/Ϫ and wild-type C57BL/6 mice upon airborne challenge with M. tuberculosis.…”

“…The enhanced level of inflammation observed in the Fc␥-chain Ϫ/Ϫ strain is not surprising because the lung bacterial burden in these mice was significantly elevated compared with that detected in wild-type mice. Because the number of neutrophils present in situ correlates well with the severity of tissue pathology in M. tuberculosis infection (38,39), studies were undertaken to enumerate this immune cell in the lungs of infected Fc␥-chain Ϫ/Ϫ mice. Not unexpectedly, quantification of neutrophil influx into the lungs revealed a significant increase in Fc␥-chain Ϫ/Ϫ mice relative to wild-type mice up to at least 15 wk after infection (Fig.…”