Disturbances in Chemokine Pathways as a Mechanism for Poor Immune Containment of MTB in the setting of HIV Co-infection

Abstract

Abstract Tuberculosis (TB) is one of the ten top causes of death worldwide and the leading cause in people living with Human Immunodeficiency Virus (HIV). The loss of function by diverse leukocyte populations and poor organization of the protective granuloma structure due to HIV infection is associated with poor immunity and increased proliferation of Mtb bacilli in co-infection. We employed our humanized mouse model of Mtb and HIV co-infection to investigate the HIV-mediated disturbances in the chemokines and chemokine receptors that regulate the recruitment, activation, and localization of inflammatory leukocytes at sites of pulmonary infection. Lung tissue of mice that were non-infected or infected with Mtb, HIV, or Mtb/HIV was used for multiplex ELISA of chemokine profiles in supernatants and for high throughput RNA sequencing to identify differential transcription of chemokine and chemokine receptor genes. Our results show that Mtb infection of humanized mouse lung activates human chemokine pathways important for recruitment and effector function of leukocytes at sites of infection such as CXCL1, CXCL5, and CCL2. Co-infection with HIV, however, activated differential transcription of several chemokines and chemokine receptor families, compared to Mtb mono-infection. These outcomes were associated with greater bacterial and viral burden in co-infected animals and may identify candidate mechanisms for host directed therapies to reduce aggressive TB in those living with HIV.