Genetically Determined Susceptibility to Tuberculosis in Mice Causally Involves Accelerated and Enhanced Recruitment of Granulocytes

Abstract

Classical twin studies and recent linkage analyses of African populations have revealed a potential involvement of host genetic factors in susceptibility or resistance to Mycobacterium tuberculosis infection. In order to identify the candidate genes involved and test their causal implication, we capitalized on the mouse model of tuberculosis, since inbred mouse strains also differ substantially in their susceptibility to infection. Two susceptible and two resistant mouse strains were aerogenically infected with 1,000 CFU of M. tuberculosis, and the regulation of gene expression was examined by Affymetrix GeneChip U74A array with total lung RNA 2 and 4 weeks postinfection. Four weeks after infection, 96 genes, many of which are involved in inflammatory cell recruitment and activation, were regulated in common. One hundred seven genes were differentially regulated in susceptible mouse strains, whereas 43 genes were differentially expressed only in resistant mice. Data mining revealed a bias towards the expression of genes involved in granulocyte pathophysiology in susceptible mice, such as an upregulation of those for the neutrophil chemoattractant LIX (CXCL5), interleukin 17 receptor, phosphoinositide kinase 3 delta, or gamma interferon-inducible protein 10. Following M. tuberculosis challenge in both airways or peritoneum, granulocytes were recruited significantly faster and at higher numbers in susceptible than in resistant mice. When granulocytes were efficiently depleted by either of two regimens at the onset of infection, only susceptible mice survived aerosol challenge with M. tuberculosis significantly longer than control mice. We conclude that initially enhanced recruitment of granulocytes contributes to susceptibility to tuberculosis.

The Pathology ofMycobacterium tuberculosisInfection

“…61 This effect has recently been shown to be due to differential chemokine expression between these 2 models and may explain the earlier discrepancies in neutrophil studies. 116 Neutrophils have also been shown to be the predominant infected cell type in active TB patients, suggesting a permissive environment for bacillary replication. 62 Type 1 and 2 pneumocytes, as well as pulmonary fibroblasts and endothelial cells, have been reported to contain mycobacterial DNA in TB patients, 98 and both pneumocytes and alveolar endothelial cells can be infected in vitro, 144 but the role of these cells in disease is unclear.…”

Expression of immunoregulatory genes in peripheral blood mononuclear cells of European wild boar immunized with BCG

“…RANTES is a proinflammatory chemokine that plays an active role in recruiting leukocytes into inflammatory sites and 25 also induces the proliferation and activation of certain natural-killer (NK) cells to form A c c e p t e d M a n u s c r i p t Vet Microbiol 9 CHAK (CC-Chemokine-activated killer) cells (Maghazachi et al, 1996). RANTES is induced by M. tuberculosis in mouse and human macrophages (Ehrt et al, 2001;Ragno et al, 2001) and in mouse lungs after aerogenic infection (Keller et al, 2006). RANTES is also weakly induced in BCG vaccinated guinea pigs (Tree et al, 2006).…”

Inflammation and Immunopathogenesis of Tuberculosis Progression

“…To elucidate whether the extent of inflammation affects TB progression in a "normal" population, several groups have compared immune responses in mice genetically resistant and susceptible to TB. In different models, susceptible mice produced more proinflammatory cytokines and developed stronger neutrophilic inflammation than resistant mice (Cardona et al, 2003;Eruslanov et al, 2004;Eruslanov et al, 2005;Keller et al, 2006). To directly address an association between inflammatory reactions and TB progression, we have recently analyzed TB severity and immune reactivity in a panel of genetically heterogeneous (A/SnxI/St)F2 hybrid mice (Lyadova et al, 2010).…”

“…In humans, high numbers of neutrophils in BAL fluids have been associated with disease activity and lung tissue cavitation (Barry et al, 2009;Sutherland et al, 2009). In mice, neutrophils (Gr-1-positive cells) accumulate abundantly in the lungs of susceptible mice (e.g., I/St, DBA/2) but are less numerous in resistant mice (Eruslanov et al, 2005;Keller et al, 2006). It is believed that neutrophils contribute to disease progression by amplifying local inflammatory reactions and mediating tissue injury.…”

“…In some studies, granulocytes from susceptible mice were shown to have intrinsically high capacity for migration in response to inflammatory stimuli (Keller et al, 2006). However, neutrophilic infiltration is a characteristic future of severe TB in hosts of different genetic backgrounds, e.g., in DBA/2, C3H, I/St, 129Sv mice.…”