Journal Article

SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

Baranowski, Tonilynn M., Karell, Paul, Rutledge, Tara, Lin, Philana Ling, Borish, H. Jacob, Flynn, JoAnne L., Brown, Jessica, Hopkins, Forrest, Maiello, Pauline, White, Alexander G., Ambrose, Zandrea, Fortune, Sarah M., Diedrich, Collin R.

2020

Overview

Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-α, IFN-γ, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to CD4 depleted animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and reduced Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Animals / Antibodies / Antigens / Biology and Life Sciences / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / Cell activation / Coinfection - immunology / Complications and side effects / Depletion / Granuloma / Granuloma - virology / Granulomas / Granzyme B / HIV / Hospitals / Human immunodeficiency virus / Immunocompromised Host - immunology / Immunology / Infections / Infectious diseases / Interleukin 10 / Interleukin 17 / Interleukin 2 / Interleukin 4 / Latent Tuberculosis - immunology / Latent Tuberculosis - virology / Lentivirus infections / Lymphatic system / Lymphocytes / Lymphocytes T / Macaca fascicularis / Medicine / Medicine and Health Sciences / Mycobacterium tuberculosis / Mycobacterium tuberculosis - immunology / Pathology / Pediatrics / Physiological aspects / Public health / Risk analysis / Risk factors / Simian Acquired Immunodeficiency Syndrome - immunology / Simian Acquired Immunodeficiency Syndrome - virology / Simian immunodeficiency virus / Simian Immunodeficiency Virus - immunology / Tuberculosis / Tumor necrosis factor / Tumor necrosis factor-TNF / Vaccines / Virus activation / Virus Activation - immunology / Viruses / α-Interferon / γ-Interferon