BCG Vaccination Prevents Reactivation of Latent Lymphatic Murine Tuberculosis Independently of CD4+ T Cells.

Harindra D Sathkumara,Andreas Kupz,Mario Alberto Flores-Valdez,Michel De Jesús Aceves-Sánchez,Saparna Pai,Natkunam Ketheesan

doi:10.3389/fimmu.2019.00532

Abstract

Tuberculosis (TB) is a major global public health problem causing significant mortality and morbidity. In addition to ~10.4 million cases of active TB annually, it is estimated that about two billion people are latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of TB. Reactivation of latent Mtb infection is the leading cause of death in patients with immunodeficiency virus (HIV) infection. The low efficiency of the only licensed anti-TB vaccine, Bacille Calmette–Guérin (BCG) to reduce pulmonary TB in adults contributes to this problem. Here we investigated if vaccination with conventional BCG or the genetically modified experimental BCGΔBCG1419c strain can prevent reactivation of latent lymphatic TB in a mouse model of induced reactivation, following the depletion of CD4+ T cells, as it occurs in HIV+ individuals. Vaccination with conventional BCG or BCGΔBCG1419c prevented reactivation of Mtb from the infected lymph node and the systemic spread of Mtb to spleen and lung. Prevention of reactivation was independent of vaccination route and was accompanied by reduced levels of circulating inflammatory cytokines and the absence of lung pathology. Our results demonstrate that vaccine-induced CD4+ T cells are not essential to prevent reactivation of latent lymphatic murine TB, and highlight the need to better understand how non-CD4+ immune cell populations participate in protective immune responses to control latent TB.

Highlights

Tuberculosis (TB) affects ∼10.4 million people annually and is associated with 1.7 million deaths per year [1]
To determine if Bacille Calmette–Guérin (BCG) vaccination can prevent reactivation of lymphatic murine latent TB infection (LTBI) following the loss of CD4+ cells, we vaccinated C57BL/6 mice with two different strains of BCG: BCG Pasteur and a BCG Pasteur strain deficient in the gene BCG1419c
Using a tractable mouse model, we provide compelling evidence that immune control of reactivation of latent lymphatic Mycobacterium tuberculosis (Mtb) infection can be independent of vaccine-induced CD4+ T cells

Summary

Introduction

Tuberculosis (TB) affects ∼10.4 million people annually and is associated with 1.7 million deaths per year [1]. The immune system usually contains Mtb infection through the formation of granulomatous lesions [2] Immunosuppressed individuals such as those who have comorbid human immunodeficiency virus (HIV) infection or diabetes mellitus have an impaired ability to control latent TB infection (LTBI) [3], resulting in active disease and transmission. It was very recently demonstrated that a higher monocyte and macrophage turnover was responsible for LTBI reactivation in macaques co-infected with Mtb and simian immunodeficiency virus (SIV) [12]. These findings further challenge the assumption that CD4+ T cells are irreplaceable in TB

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Results

Conclusion