Abstract
Brucellosis is a common zoonotic disease that remains endemic in many parts of the world. Dissecting the host immune response during this disease provides insight as to why brucellosis is often difficult to resolve. We used a Brucella epitope specific in vivo killing assay to investigate the ability of CD8+ T cells to kill targets treated with purified pathogenic protein. Importantly, we found the pathogenic protein TcpB to be a novel effector of adaptive immune evasion by inhibiting CD8+ T cell killing of Brucella epitope specific target cells in mice. Further, BALB/c mice show active Brucella melitensis infection beyond one year, many with previously unreported focal infection of the urogenital area. A fraction of CD8+ T cells show a CD8+ Tmem phenotype of LFA-1hi, CD127hi, KLRG-1lo during the course of chronic brucellosis, while the CD8+ T cell pool as a whole had a very weak polyfunctional cytokine response with diminished co-expression of IFN-γ with TNFα and/or IL-2, a hallmark of exhaustion. When investigating the expression of these 3 cytokines individually, we observed significant IFN-γ expression at 90 and 180 days post-infection. TNFα expression did not significantly exceed or fall below background levels at any time. IL-2 expression did not significantly exceeded background, but, interestingly, did fall significantly below that of uninfected mice at 180 days post-infection. Brucella melitensis evades and blunts adaptive immunity during acute infection and our findings provide potential mechanisms for the deficit observed in responding CD8+ T cells during chronic brucellosis.
Highlights
Brucella spp. are the cause of the most common zoonotic disease in man
BALB/c mice have long been used as the susceptible model of brucellosis, yet there remains the uncertainty that Brucella infection of mice may not be similar to a natural host [6,16,54]
We present evidence of: 1) chronic infection in BALB/c mice for greater than 1 year, 2) a low level of CD8+ Tmem cells, 3) lack of polyfunctional cytokine production, and 4) the B. melitensis protein TcpB inhibits in vivo cytotoxic CD8+ T killing of Brucella peptide expressing target cells
Summary
Brucella spp. are the cause of the most common zoonotic disease in man. There are approximately 500,000 new cases diagnosed each year, with endemic disease flourishing in the Middle East, Mediterranean basin, Northern Africa, and across the Asian continent. Over its extremely long history as a human pathogen, Brucella has evolved some impressive and redundant mechanisms to evade innate immunity [7,8] These include blocking activation of NFkB by mimicking a host protein, producing a non-reactive LPS, using phagosome acidification to its advantage, and inhibiting phagosome-lysosome fusion [9,10,11,12,13,14]. These known mechanisms along with additional unknown disruptors of the adaptive immune response contribute to its low infectious dose where 20 bacteria ensure an ID90 in humans [15]. Uncovering more of the particulars of the CD8+ T cell mediated response, for example specific surface phenotypes, factors produced, cellular interactions, and cytotoxic T cell killing of cells expressing Brucella peptides will provide needed insight for successful and safe vaccine design [16,17,18]
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