Abstract
BackgroundThe roles of host and pathogen factors in determining innate immune responses to M. tuberculosis are not fully understood. In this study, we examined host macrophage immune responses of 3 race/ethnic groups to 3 genetically and geographically diverse M. tuberculosis lineages.MethodsMonocyte-derived macrophages from healthy Filipinos, Chinese and non-Hispanic White study participants (approximately 45 individuals/group) were challenged with M. tuberculosis whole cell lysates of clinical strains Beijing HN878 (lineage 2), Manila T31 (lineage 1), CDC1551 (lineage 4), the reference strain H37Rv (lineage 4), as well as with Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA) and TLR4 agonist lipopolysaccharide (TLR4/LPS). Following overnight incubation, multiplex assays for nine cytokines: IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα, and GM-CSF, were batch applied to supernatants.ResultsFilipino macrophages produced less IL-1, IL-6, and more IL-8, compared to macrophages from Chinese and Whites. Race/ethnicity had only subtle effects or no impact on the levels of IL-10, IL-12p70, TNFα and GM-CSF. In response to the Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA), Filipino macrophages again had lower IL-1 and IL-6 responses and a higher IL-8 response, compared to Chinese and Whites. The TLR2/LTA-stimulated Filipino macrophages also produced lower amounts of IL-10, TNFα and GM-CSF. Race/ethnicity had no impact on IL-12p70 levels released in response to TLR2/LTA. The responses to TLR4 agonist lipopolysaccharide (TLR4/LPS) were similar to the TLR2/LTA responses, for IL-1, IL-6, IL-8, and IL-10. However, TLR4/LPS triggered the release of less IL-12p70 from Filipino macrophages, and less TNFα from White macrophages.ConclusionsBoth host race/ethnicity and pathogen strain influence the innate immune response. Such variation may have implications for the development of new tools across TB therapeutics, immunodiagnostics and vaccines.
Highlights
Genotyping of Mycobacterium tuberculosis (M. tuberculosis) has shown that lineages of the organism have predilections for certain geographic distributions and dominate certain geographic areas [1,2,3,4]
Race/ethnicity had no impact on IL-12p70 levels released in response to TLR2/LTA
The discovery of Toll-like receptors (TLR) polymorphisms that are associated with race/ethnicity and response to particular pathogens, raises the distinct possibility that there are ethnicity-specific differences in TLR2 and/or TLR4, resulting in differential innate responses to M. tuberculosis strains [12,13,14,15,16]
Summary
Genotyping of Mycobacterium tuberculosis (M. tuberculosis) has shown that lineages of the organism have predilections for certain geographic distributions and dominate certain geographic areas [1,2,3,4]. Members of the East Asian lineage (that includes the Beijing family) are predominant in East Asia, members of the Indo-Oceanic lineage are predominant in the Philippines and around the rim of the Indian Ocean [5], and members of the M. africanum West Africa I and II are largely restricted to West Africa [1, 6] This global distribution of strains may not be random or based solely upon variabilities in virulence, but may be partly determined by the genetics, epigenetics and other factors of the host and the microbe, both of which are under natural selection forces. The discovery of TLR polymorphisms that are associated with race/ethnicity and response to particular pathogens, raises the distinct possibility that there are ethnicity-specific differences in TLR2 and/or TLR4, resulting in differential innate responses to M. tuberculosis strains [12,13,14,15,16]. We examined host macrophage immune responses of 3 race/ethnic groups to 3 genetically and geographically diverse M. tuberculosis lineages
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