Project Summary
Human tuberculosis (TB) is caused mainly by Mycobacterium tuberculosis (Mtb) and represents an enormous
challenge to global health because of the inadequacy of currently available drugs and vaccines. The most
common clinical manifestation is pulmonary TB, and Bacille Calmette Guerin (BCG) is the only licensed vaccine
for protection against TB; however, its efficacy is highly variable. Today at least 52 countries have reported
multidrug-resistant (MDR) and extensive drug-resistant (XDR) TB cases which cannot be cured or contained by
current TB therapy. Thus, there is an urgent need to develop new therapies/vaccines that effectively prevent or
cure TB. It is well established that the generation of an adaptive immune response against Mtb occurs inside
germinal centers (GCs) in secondary lymphoid organs (SLOs), such as spleen and lesion draining lymph nodes,
where antigen‐presenting cells (APCs) and antigen-specific circulating T and B lymphocytes interact, clonally
expand, and are disseminated to sites of infection. We found that mice vaccinated with BCG and exposed to
Mycobacterium avium [a non-tuberculous mycobacterium (NTM)] via drinking water provide more robust and
longer-term protection than BCG alone as determined by reduced Mtb bacterial burden and inflammatory
progression of infection. Interestingly, these mice also developed ectopic germinal centers (eGC) in the lungs
and have an increased number of B-cells and higher levels of anti-Mtb cell lysate-specific IgA and IgG antibodies.
These findings suggest that NTM and B-cells play a critical role in generating protective immunity against
pulmonary Mtb infection, and the formation of eGC in these mice is a crucial factor in this improved immunity.
Thus, investigating the mechanism of eGC formation and the role of NTM and B-cells in its stimulation is an
important question to understand TB pathogenesis and develop effective vaccines and therapies. In this K99/R00
application, we propose three aims: 1) investigating the key differences between eGC in lungs and conventional
GCs in lymph nodes, 2) evaluating the role of NTM and B-cells in eGC stimulation, and 3) characterizing the
antigen-specificity and affinity of eGC B-cells against Mtb antigens. The results of this proposal will bring us one
step closer to understanding the B-cell and antibody-mediated mechanisms of protection from TB.
