Cytokine responses and progression to active tuberculosis in HIV-1-infected Ugandans: A prospective study
Identifying correlates of immunity or susceptibility to disease promotes understanding of pathogenesis and development of
diagnostic tools, treatments, and vaccines. There is evidence that type 1 cytokine responses are associated with protection
against tuberculosis, and suppression of type 1, or switching to type 2 responses, with susceptibility, but this has not been
studied prospectively. We studied a cohort of 631 HIV-1-infected Ugandan adults. At enrolment we performed whole blood cultures
for type 1 (interferon [IFN]-γ, interleukin [IL]-2) and type 2/immunosuppressive (IL-5, IL-10) responses to mycobacterial
antigens (purified protein derivative [PPD] and culture filtrate proteins [CFP]). The incidence of tuberculosis was not associated
with IFN-γ responses, but was higher among participants with IL-2 responses (adjusted rate ratios [RR]: PPD 3.48; CFP 3.99;
P < 0.001). For tuberculin skin test-positive participants, high incidence was also associated with an IL-10 response to PPD
(adjusted RR 6.24, P = 0.03); for those with a BCG scar, high incidence was associated with positive IL-5 responses (adjusted RRs: PPD 3.64, P = 0.006; CFP 3.44, P = 0.04). The association with IL-2 production may reflect a response to tuberculous infection or to activating disease; the
associations with IL-10 and IL-5 are in keeping with the expected role of immunosuppressive or type 2 cytokines.
Available from: Ben Marais
- "CD4 T cells are key antimycobacterial components of the adaptive immune response [20, 154–157], and TB is a leading cause of death in CD4 T cell lymphopenic HIV patient . Key cytokines elaborated by protective Th1 effector cells include IFN-γ and TNF [20, 154–156] although CD4 T cells can also restrict M.tb replication by an IFNγ- and TNF-independent mechanism in mice . "
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ABSTRACT: One of the challenges faced by the infant immune system is learning to distinguish the myriad of foreign but nonthreatening antigens encountered from those expressed by true pathogens. This balance is reflected in the diminished production of proinflammatory cytokines by both innate and adaptive immune cells in the infant. A downside of this bias is that several factors critical for controlling Mycobacterium tuberculosis infection are significantly restricted in infants, including TNF, IL-1, and IL-12. Furthermore, infant T cells are inherently less capable of differentiating into IFN- γ -producing T cells. As a result, infected infants are 5-10 times more likely than adults to develop active tuberculosis (TB) and have higher rates of severe disseminated disease, including miliary TB and meningitis. Infant TB is a fundamentally different disease than TB in immune competent adults. Immunotherapeutics, therefore, should be specifically evaluated in infants before they are routinely employed to treat TB in this age group. Modalities aimed at reducing inflammation, which may be beneficial for adjunctive therapy of some forms of TB in older children and adults, may be of no benefit or even harmful in infants who manifest much less inflammatory disease.
Available from: Isabella Cattadori
- "An alternative indirect route of interaction may also occur when a parasite secretes compounds that influence another parasite species or may induce physiological changes in the host that alter the survival of the second species but this route seems relatively uncommon in natural systems (Behnke et al., 2001; Cox, 2001). One inference from these observations is that immunemediated species interactions can drive variation in susceptibility and infectiousness between individual hosts and consequently shape the parasite community of a host population (Hershow et al., 1997; Nacher et al., 2002; Elliott et al., 2004; Andreansky et al., 2005; Graham et al., 2005; Thorburn et al., 2006; Cattadori et al., 2007). For example, if variation in susceptibility is influenced not only by past and current exposure to the focal parasite but also to the presence and history of infection of the second species , this will increase variation in intensity between hosts and the overall pattern of parasite distribution in the whole host population (Boag et al., 2001). "
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ABSTRACT: We examined the hypothesis that the interaction between concomitant infecting parasites modifies host susceptibility, parasite intensity and the pattern of parasite distribution within the host population. We used a 26 year time series of three common parasites in a natural population of rabbits: two gastrointestinal nematodes (Trichostrongylus retortaeformis and Graphidium strigosum) and the immunosuppressive myxoma virus. The frequency distribution of nematodes in the host population and the relationship between host age and nematode intensity were explored in rabbits with either single or dual nematode infections and rabbits infected with the nematodes and myxoma virus. The aggregation of T. retortaeformis and G. strigosum among the rabbits varied with the nature of the co-infection both in male and female hosts. The two nematodes exhibited different age-intensity profiles: G. strigosum intensity increased exponentially with host age while T. retortaeformis intensity exhibited a convex shape. The presence of a secondary infection did not change the age-intensity profile for G. strigosum but for T. retortaeformis co-infection (either both nematodes or myxoma-nematodes) resulted in significantly greater intensities in adult hosts. Results suggest that multi-species infections contributed to aggregation of parasites in the host population and to seasonal variation in intensity, but also enhanced differences in parasitism between sexes. This effect was apparent for T. retortaeformis, which appears to elicit a strong acquired immune response but not for G. strigosum which does not produce any evident immune reaction. We concluded that concomitant infections mediated by host immunity are important in modifying host susceptibility and influencing heterogeneity amongst individual hosts.
Available from: Linda-Gail Bekker
- "Whole blood assays were done using a methodology similar to that described previously [27,28]. Heparinized whole blood was diluted 5-fold using RPMI 1640 supplemented with penicillin, streptomycin and 2 mM L-glutamine and was plated into 96-well plates in the presence of antigen or mitogen or left unstimulated. "
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ABSTRACT: Interferon-gamma (IFN-gamma) ELISPOT assays incorporating Mycobacterium tuberculosis-specific antigens are useful in the diagnosis of tuberculosis (TB) or latent infection. However, their utility in patients with advanced HIV is unknown. We studied determinants of ELISPOT responses among patients with advanced HIV infection (but without active TB) living in a South African community with very high TB notification rates.
IFN-gamma responses to ESAT-6 and CFP-10 in overnight ELISPOT assays and in 7-day whole blood assays (WBA) were compared in HIV-infected patients (HIV+, n = 40) and healthy HIV-negative controls (HIV-, n = 30) without active TB. Tuberculin skin tests (TSTs) were also done.
ELISPOTs, WBAs and TSTs were each positive in >70% of HIV- controls, reflecting very high community exposure to M. tuberculosis. Among HIV+ patients, quantitative WBA responses and TSTs (but not the proportion of positive ELISPOT responses) were significantly impaired in those with CD4 cell counts <100 cells/mul compared to those with higher counts. In contrast, ELISPOT responses (but not WBA or TST) were strongly related to history of TB treatment; a much lower proportion of HIV+ patients who had recently completed treatment for TB (n = 19) had positive responses compared to those who had not been treated (11% versus 62%, respectively; P < 0.001). Multivariate analysis confirmed that ELISPOT responses had a strong inverse association with a history of recent TB treatment (adjusted OR = 0.06, 95%CI = 0.10-0.40, P < 0.01) and that they were independent of CD4 cell count and viral load. Among HIV+ individuals who had not received TB treatment both the magnitude and proportion of positive ELISPOT responses (but not TST or WBA) were similar to those of HIV-negative controls.
The proportion of positive ELISPOT responses in patients with advanced HIV infection was independent of CD4 cell count but had a strong inverse association with history of TB treatment. This concurs with the previously documented low TB risk among patients in this cohort with a history of recent treatment for TB. These data suggest ELISPOT assays may be useful for patient assessment and as an immuno-epidemiological research tool among patients with advanced HIV and warrant larger scale prospective evaluation.
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