Mycobacterial Antigens Exacerbate Disease Manifestations inMycobacterium tuberculosis-Infected Mice

Abstract

To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-␣) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-␣, and to a lesser extent, IL-2 and gamma interferon (IFN-␥), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-␣ resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-␣-induced inflammation without reducing the bacillary load.

Lactoferrin modulation of IL-12 and IL-10 response from activated murine leukocytes

“…During MTB infection, TNF-α and IL-6 work in concert to initiate and influence the development of the granulomatous response, an organization of cellular infiltrate at the site of infection important in containment of bacteria [2,4,20,33,38]. However, TNF-α and IL-6 are also involved in directing the generation of the T H 1 response, but unlike IL-12, they are indirectly involved in suppressing T H 1 responses.…”

Do successful tuberculosis vaccines need to be immunoregulatory rather than merely Th1-boosting?

“…This regulatory approach to vaccine design will be particularly relevant to therapeutic vaccination. Th1-inducing vaccines make ongoing disease worse [32,33].…”

Inflammation and Immunopathogenesis of Tuberculosis Progression

“…As mentioned above, simultaneous blocking of IL-1 and TNF- significantly prolonged survival of Tir-8-/-mice, and neutralization of G-CSF or depletion of neutrophils decreased disease severity in CARD9-/-mice (Garlanda et al, 2007;Dorhoi et al, 2010). In contrast to anti-TNF treatment, treatment of mice with TNF- or BCG expressing TNF- significantly increased lung tissue inflammation and resulted in accelerated mortality without affecting the bacillary load (Moreira et al, 2002). Altogether, the studies show that dampening immune inflammation during TB may significantly ameliorate disease outcome without affecting Mtb replication.…”

“…However, inflammatory reactions may also be deleterious and promote disease exacerbation. The first indication of a damaging role of host immune response during TB was obtained by Koch who described local and systemic reactions and disease worsening following treatment of TB patients with Mtb extract (Koch, 1890, as cited in Moreira et al, 2002). Thereafter, multiple observations have associated severe TB course with high inflammatory reactions.…”