No abstract

Challenge with low doses of LPS together with d-galactosamine causes severe liver injury, resulting in lethal shock (low dose LPS-induced shock). We examined the role of LFA-1 in low dose LPS-induced shock. LFA-1−/− mice were more resistant to low dose LPS-induced shock/liver injury than their heterozygous littermates, although serum levels of TNF-α and IL-12 were higher in these mice. C57BL/6 mice were not rescued from lethal effects of LPS by depletion of NK1+ cells, granulocytes, or macrophages, and susceptibility of NKT cell-deficient mice was comparable to that of controls. High numbers of platelets were detected in the liver of LFA-1+/− mice after low dose LPS challenge, whereas liver accumulation of platelets was only marginal in LFA-1−/− mice. Following low dose LPS challenge, serum levels of IL-10 were higher in LFA-1−/− mice than in LFA-1+/− mice, and susceptibility to low dose LPS-induced shock as well as platelet accumulation in the liver of LFA-1−/− mice were markedly increased by IL-10 neutralization. Serum levels of IL-10 in LFA-1+/− mice were only marginally affected by macrophage depletion. However, in LFA-1−/− mice macrophage depletion markedly reduced serum levels of IL-10, and as a corollary, susceptibility of LFA-1−/− mice to low dose LPS-induced shock was markedly elevated despite the fact that TNF-α levels were also diminished. We conclude that LFA-1 participates in LPS-induced lethal shock/liver injury by regulating IL-10 secretion from macrophages and that IL-10 plays a decisive role in resistance to shock/liver injury. Our data point to a novel role of LFA-1 in control of the proinflammatory/anti-inflammatory cytokine network.

Infection with Mycobacterium tuberculosis (Mtb) is the leading cause of death in human immunodeficiency virus (HIV)+ individuals, particularly in Sub-Saharan Africa. Management of this deadly co-infection is a significant global health challenge that is exacerbated by the lack of efficient vaccines against both Mtb and HIV, as well as the lack of reliable and robust animal models for Mtb/HIV co-infection. Here we describe a tractable and reproducible mouse model to study the reactivation dynamics of latent Mtb infection following the loss of CD4+ T cells as it occurs in HIV-co-infected individuals. Whereas intradermally (i.d.) infected C57BL/6 mice contained Mtb within the local draining lymph nodes, depletion of CD4+ cells led to progressive systemic spread of the bacteria and induction of lung pathology. To interrogate whether reactivation of Mtb after CD4+ T cell depletion can be reversed, we employed interleukin (IL)-2/anti-IL-2 complex-mediated cell boost approaches. Although populations of non-CD4 lymphocytes, such as CD8+ memory T cells, natural killer (NK) cells and double-negative (DN) T cells significantly expanded after IL-2/anti-IL-2 complex treatment, progressive development of bacteremia and pathologic lung alterations could not be prevented. These data suggest that the failure to reverse Mtb reactivation is likely not due to anergy of the expanded cell subsets and rather indicates a limited potential for IL-2-complex-based therapies in the management of Mtb/HIV co-infection.

Tuberculosis (TB) remains a global health threat. Although it is generally accepted that TB results from intensive cross-talk between the host and the pathogen Mycobacterium tuberculosis, underlying mechanisms remain elusive. The first evidence of human polymorphisms related to susceptibilities to distinct M. tuberculosis lineages has been gathered. Confrontation of limited host resistance with heightened bacterial virulence forms a most hazardous combination. We investigated extreme combinations, confronting inducible nitric oxide synthase-deficient (iNOS(-/-)) and wild-type (WT) mice with 2 related M. tuberculosis strains that differ markedly in virulence, namely, the M. tuberculosis laboratory strains H37Rv and H37Ra. We provide evidence that deregulated chemokine signaling and excessive neutrophil necrosis contribute to disproportionate neutrophil influx and exacerbated TB in iNOS(-/-) mice infected with virulent M. tuberculosis (strain H37Rv), whereas resistant and susceptible mice controlled attenuated H37Ra equally well. Thus, a combination of host susceptibility and M. tuberculosis virulence determines the role of iNOS in the protection and control of inflammation.