Oral Vaccination with Heat Inactivated Mycobacterium bovis Activates the Complement System to Protect against Tuberculosis

Abstract

Tuberculosis (TB) remains a pandemic affecting billions of people worldwide, thus stressing the need for new vaccines. Defining the correlates of vaccine protection is essential to achieve this goal. In this study, we used the wild boar model for mycobacterial infection and TB to characterize the protective mechanisms elicited by a new heat inactivated Mycobacterium bovis vaccine (IV). Oral vaccination with the IV resulted in significantly lower culture and lesion scores, particularly in the thorax, suggesting that the IV might provide a novel vaccine for TB control with special impact on the prevention of pulmonary disease, which is one of the limitations of current vaccines. Oral vaccination with the IV induced an adaptive antibody response and activation of the innate immune response including the complement component C3 and inflammasome. Mycobacterial DNA/RNA was not involved in inflammasome activation but increased C3 production by a still unknown mechanism. The results also suggested a protective mechanism mediated by the activation of IFN-γ producing CD8+ T cells by MHC I antigen presenting dendritic cells (DCs) in response to vaccination with the IV, without a clear role for Th1 CD4+ T cells. These results support a role for DCs in triggering the immune response to the IV through a mechanism similar to the phagocyte response to PAMPs with a central role for C3 in protection against mycobacterial infection. Higher C3 levels may allow increased opsonophagocytosis and effective bacterial clearance, while interfering with CR3-mediated opsonic and nonopsonic phagocytosis of mycobacteria, a process that could be enhanced by specific antibodies against mycobacterial proteins induced by vaccination with the IV. These results suggest that the IV acts through novel mechanisms to protect against TB in wild boar.

Increased Lytic Efficiency of Bovine Macrophages Trained with Killed Mycobacteria

“…This suggests a new mechanism of immune protection by which low-intensity priming enhances early phagocytic responses independently of humoral and cellular adaptive immune responses for, at least, six months. This mechanism would support the empirical evidence of protection induced by killed mycobacterial vaccines [3,4,5]. These findings fit well with the recently proposed general concept of trained immunity, which was developed to explain the observation that innate immune responses provide unspecific protection against pathogens including other than those that originally triggered the immune response.…”

“…The blood samples were analysed using an in-house anti- M . bovis ELISA with bovine PPD as the antigen [5]. This assay includes a serum Mycobacterium phlei pre-absorption step to reduce non-specific reactivity caused by environmental mycobacteria.…”

Tonsils of the Soft Palate Do Not Mediate the Response of Pigs to Oral Vaccination with Heat-Inactivated Mycobacterium bovis

“…In general terms, the pigs showed more severe lesions after challenge with field M. bovis than wild boar challenged with similar doses in previous trials (17,35,36). Also, abdominal lesions were more evident in pigs.…”

An overview of tuberculosis plant-derived vaccines

“…It has been found that oral immunization with a new heat inactivated Mycobacterium bovis vaccine protects in terms of culture and lesion scores, particularly in the respiratory tract. These findings make this model a promising tool for reaching the goal of preventing TB pulmonary disease [80]. Mechanisms that correlated with these effects were associated with humoral responses, the complement component C3 and inflammasome.…”