The Innate Immune Response toMycobacterium tuberculosisInfection

Abstract

Infection with Mycobacterium tuberculosis causes >1.5 million deaths worldwide annually. Innate immune cells are the first to encounter M. tuberculosis, and their response dictates the course of infection. Dendritic cells (DCs) activate the adaptive response and determine its characteristics. Macrophages are responsible both for exerting cell-intrinsic antimicrobial control and for initiating and maintaining inflammation. The inflammatory response to M. tuberculosis infection is a double-edged sword. While cytokines such as TNF-α and IL-1 are important for protection, either excessive or insufficient cytokine production results in progressive disease. Furthermore, neutrophils—cells normally associated with control of bacterial infection—are emerging as key drivers of a hyperinflammatory response that results in host mortality. The roles of other innate cells, including natural killer cells and innate-like T cells, remain enigmatic. Understanding the nuances of both cell-intrinsic control of infection and regulation of inflammation will be crucial for the successful development of host-targeted therapeutics and vaccines. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Mycobacterium tuberculosis Exploits Focal Adhesion Kinase to Induce Necrotic Cell Death and Inhibit Reactive Oxygen Species Production

“…Since lack of cell death is not by itself a direct antibacterial response, we sought to identify alternative mechanisms/pathways that would explain the increased ability of FAK overexpression macrophages to restrict intracellular Mtb survival. Host cells use antibacterial mechanisms such as increased induction of ROS and reactive nitrogen intermediates (RNI) to control Mtb growth and survival ( 6 , 26 ). Interestingly, studies have reported that FAK plays a crucial role in NADPH oxidase-dependent ROS production to reduce the survival of Escherichia.…”

“…However, IL-10 also provides a host-protective role in restraining hyperinflammation to prevent excessive tissue damage during specific phases of TB disease ( 93 , 95 ). In contrast, TNF-α and IL-1β are generally considered to be essential for the control of TB infection; however, excess levels can be detrimental to the host by causing macrophage cell death and subsequent hyperinflammation ( 26 ). Taken together, our findings suggest that FAK is associated with reduced inflammation during TB infection, whereas inhibition of FAK increases inflammation.…”

“…This question was compelling when considering the mechanism of how FAK overexpression results in reduced Mtb survival relative to control macrophages ( Figures 6B, C ). To eliminate Mtb during infection, host cells trigger a range of antibacterial responses, including increased induction of ROS ( 6 ), RNI ( 26 ), phagosome maturation ( 107 ), autophagy ( 10 ), and efferocytosis ( 108 ). Our data suggest a new role for FAK in the generation of ROS to control intracellular Mtb survival ( Figures 7A, B ).…”

“…Cell death is a consequence of the interactions between the bacteria and the host cell ( 23 ). It can greatly influence disease progression by promoting either the survival or clearance of the invading pathogen ( 24 – 26 ). Mtb - infected macrophages can undergo two main modes of cell death: apoptosis and necrosis ( 27 ), the latter of which includes both passive and programmed forms of cell death.…”

Insilico Designing of a Chimeric Vaccine Using EIS (Rv2416c) Protein Against Mycobacterium Tuberculosis H37Rv; An Immunoinformatics Approach

“…Progression of TB is associated with the host response to Mtb infection. The innate immune cells including the macrophages, dendritic cells and the natural cells play a key role in determining the course of infection as they are the rst to confront the Mtb pathogen, upon infection [6]. Once the disease progresses, the active T cells (CD4 + and CD8 + ) move to the lungs and interact with the antigen presenting cells.…”