59 research outputs found
Suboptimal Activation of Antigen-Specific CD4+ Effector Cells Enables Persistence of M. tuberculosis In Vivo
Adaptive immunity to Mycobacterium tuberculosis controls
progressive bacterial growth and disease but does not eradicate infection. Among
CD4+ T cells in the lungs of M.
tuberculosis-infected mice, we observed that few produced IFN-γ
without ex vivo restimulation. Therefore, we hypothesized that one mechanism
whereby M. tuberculosis avoids elimination is by limiting
activation of CD4+ effector T cells at the site of infection in
the lungs. To test this hypothesis, we adoptively transferred Th1-polarized
CD4+ effector T cells specific for M.
tuberculosis Ag85B peptide 25 (P25TCRTh1 cells), which trafficked
to the lungs of infected mice and exhibited antigen-dependent IFN-γ
production. During the early phase of infection, ∼10% of P25TCRTh1
cells produced IFN-γ in vivo; this declined to <1% as infection
progressed to chronic phase. Bacterial downregulation of fbpB
(encoding Ag85B) contributed to the decrease in effector T cell activation in
the lungs, as a strain of M. tuberculosis engineered to express
fbpB in the chronic phase stimulated P25TCRTh1 effector
cells at higher frequencies in vivo, and this resulted in CD4+ T
cell-dependent reduction of lung bacterial burdens and prolonged survival of
mice. Administration of synthetic peptide 25 alone also increased activation of
endogenous antigen-specific effector cells and reduced the bacterial burden in
the lungs without apparent host toxicity. These results indicate that
CD4+ effector T cells are activated at suboptimal
frequencies in tuberculosis, and that increasing effector T cell activation in
the lungs by providing one or more epitope peptides may be a successful strategy
for TB therapy
A Critical Role for CD8 T Cells in a Nonhuman Primate Model of Tuberculosis
The role of CD8 T cells in anti-tuberculosis immunity in humans remains unknown, and studies of CD8 T cell–mediated protection against tuberculosis in mice have yielded controversial results. Unlike mice, humans and nonhuman primates share a number of important features of the immune system that relate directly to the specificity and functions of CD8 T cells, such as the expression of group 1 CD1 proteins that are capable of presenting Mycobacterium tuberculosis lipids antigens and the cytotoxic/bactericidal protein granulysin. Employing a more relevant nonhuman primate model of human tuberculosis, we examined the contribution of BCG- or M. tuberculosis-elicited CD8 T cells to vaccine-induced immunity against tuberculosis. CD8 depletion compromised BCG vaccine-induced immune control of M. tuberculosis replication in the vaccinated rhesus macaques. Depletion of CD8 T cells in BCG-vaccinated rhesus macaques led to a significant decrease in the vaccine-induced immunity against tuberculosis. Consistently, depletion of CD8 T cells in rhesus macaques that had been previously infected with M. tuberculosis and cured by antibiotic therapy also resulted in a loss of anti-tuberculosis immunity upon M. tuberculosis re-infection. The current study demonstrates a major role for CD8 T cells in anti-tuberculosis immunity, and supports the view that CD8 T cells should be included in strategies for development of new tuberculosis vaccines and immunotherapeutics
Extreme Weather and Civil War in Somalia: Does Drought Fuel Conflict through Livestock Price Shocks?
Genome-Wide Screen for Mycobacterium tuberculosis Genes That Regulate Host Immunity
In spite of its highly immunogenic properties, Mycobacterium tuberculosis (Mtb) establishes persistent infection in otherwise healthy individuals, making it one of the most widespread and deadly human pathogens. Mtb's prolonged survival may reflect production of microbial factors that prevent even more vigorous immunity (quantitative effect) or that divert the immune response to a non-sterilizing mode (qualitative effect). Disruption of Mtb genes has produced a list of several dozen candidate immunomodulatory factors. Here we used robotic fluorescence microscopy to screen 10,100 loss-of-function transposon mutants of Mtb for their impact on the expression of promoter-reporter constructs for 12 host immune response genes in a mouse macrophage cell line. The screen identified 364 candidate immunoregulatory genes. To illustrate the utility of the candidate list, we confirmed the impact of 35 Mtb mutant strains on expression of endogenous immune response genes in primary macrophages. Detailed analysis focused on a strain of Mtb in which a transposon disrupts Rv0431, a gene encoding a conserved protein of unknown function. This mutant elicited much more macrophage TNFα, IL-12p40 and IL-6 in vitro than wild type Mtb, and was attenuated in the mouse. The mutant list provides a platform for exploring the immunobiology of tuberculosis, for example, by combining immunoregulatory mutations in a candidate vaccine strain
Dendritic Cells in Chronic Mycobacterial Granulomas Restrict Local Anti-Bacterial T Cell Response in a Murine Model
Background: Mycobacterium-induced granulomas are the interface between bacteria and host immune response. During acute infection dendritic cells (DCs) are critical for mycobacterial dissemination and activation of protective T cells. However, their role during chronic infection in the granuloma is poorly understood. Methodology/Principal Findings: We report that an inflammatory subset of murine DCs are present in granulomas induced by Mycobacteria bovis strain Bacillus Calmette-guerin (BCG), and both their location in granulomas and costimulatory molecule expression changes throughout infection. By flow cytometric analysis, we found that CD11c + cells in chronic granulomas had lower expression of MHCII and co-stimulatory molecules CD40, CD80 and CD86, and higher expression of inhibitory molecules PD-L1 and PD-L2 compared to CD11c + cells from acute granulomas. As a consequence of their phenotype, CD11c + cells from chronic lesions were unable to support the reactivation of newly-recruited, antigen 85Bspecific CD4 + IFNc + T cells or induce an IFNc response from naïve T cells in vivo and ex vivo. The mechanism of this inhibition involves the PD-1:PD-L signaling pathway, as ex vivo blockade of PD-L1 and PD-L2 restored the ability of isolated CD11c + cells from chronic lesions to stimulate a protective IFNc T cell response. Conclusions/Significance: Our data suggest that DCs in chronic lesions may facilitate latent infection by down-regulating protective T cell responses, ultimately acting as a shield that promotes mycobacterium survival. This DC shield may explai
Can Integrated Agriculture-Nutrition Programs Change Gender Norms on Land and Asset Ownership? Evidence from Burkina Faso
Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice
Social Network Capital, Economic Mobility and Poverty Traps
The paper explores the role social network capital might play in facilitating poor agents’ escape from poverty traps. We model endogenous network formation among households heterogeneously endowed with both traditional and social network capital who make investment and technology choices over time in the absence of financial markets and faced with multiple production technologies featuring different fixed costs and returns. We show that social network capital can serve as either a complement to or a substitute for productive assets in facilitating some poor households’ escape from poverty. However, the voluntary nature of costly social network formation also creates both involuntary and voluntary exclusionary mechanisms that impede some poor households’ efforts to exit poverty. The ameliorative potential of social networks therefore depends fundamentally on the underlying wealth distribution in the economy. In some settings, targeted public transfers to the poor can crowd-in private resources by inducing new social links that the poor can exploit to escape from poverty
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