Chronic pulmonary cavitary tuberculosis in rabbits: a failed host immune response

Abstract

The molecular determinants of the immune response to Mycobacterium tuberculosis HN878 infection in a rabbit model of pulmonary cavitary tuberculosis were studied. Aerosol infection of rabbits resulted in a highly differentially expressed global transcriptome in the lungs at 2 weeks, which dropped at 4 weeks and then gradually increased. While IFNγ was progressively upregulated throughout the infection, several other genes in the IFNγ network were not. T-cell activation network genes were gradually upregulated and maximally induced at 12 weeks. Similarly, the IL4 and B-cell activation networks were progressively upregulated, many reaching high levels between 12 and 16 weeks. Delayed peak expression of genes associated with macrophage activation and Th1 type immunity was noted. Although spleen CD4+ and CD8+ T cells showed maximal tuberculosis antigen-specific activation by 8 weeks, macrophage activation in lungs, lymph nodes and spleen did not peak until 12 weeks. In the lungs, infecting bacilli grew exponentially up to 4 weeks, followed by a steady-state high bacillary load to 12 weeks that moderately increased during cavitation at 16 weeks. Thus, the outcome of HN878 infection of rabbits was determined early during infection by a suboptimal activation of innate immunity and delayed T-cell activation.

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

“…Adoptive cell transfer studies in the TDM-induced granuloma model have indicated a major role of the CD4 + T lymphocytes in induction of tissue injury [190]. In line with a role of T cell immunity in cavity formation, rabbits are not protected from cavitation by progressive T cell activation during experimental TB [59]. The Mtb replication inversely correlates with frequencies of antigen-specific Th1 and Th17 cells within granulomatous lesions [191].…”

“…In how far B lymphocytes impact on TB as antibody producers or as cytokinesecreting regulatory B cells, or both, remains to be established [147,148]. Moreover, whether B lymphocytes limit exuberant inflammation [149] or promote lung pathology [59,150] awaits clarification. Balanced responses, e.g., abundance of TNF, and proper location, e.g., positioning of T cells in proximity of infected macrophages, are critical for granuloma stability.…”

“…Paucity of lymphocytes likely explains massive bacillary replication at the cavity wall [60]. However, in animal models, strength of the DTH correlates with cavity formation [59,189] and with the protease imbalance [177]. Adoptive cell transfer studies in the TDM-induced granuloma model have indicated a major role of the CD4 + T lymphocytes in induction of tissue injury [190].…”

“…Local abundance of proinflammatory mediators, such as IL-1 cognates [57], or their cross-regulation with IFN-I affects integrity of the respiratory tissue and bacillary burden [58]. Bacilli are present also at the cavity wall [9,59,60] and several hypotheses have been advanced regarding initiation of this hyperinflammatory and tissue-damaging event. Clearly, triggers for and consequences of Mtb compartmentalization in pulmonary lesions, such as granulomas, foci of pneumonia and cavities, are less well-defined compared to analogous events at the cellular scale as detailed earlier.…”

“…Studies in guinea pigs [178] and mice [179][180][181] further indicate that breakdown of lung collagen is essential for necrosis, which likely precedes cavitation. MMP-1 and other MMP cognates are abundant in respiratory secretions of patients and of animals developing cavitation [59,170,182,183]. Major sources of MMP-1 are macrophages [170].…”