Mitochondrial DNA and the Immuno-inflammatory Response: New Frontiers to Control Specific Microbial Diseases

Mitochondria are highly relevant organelles with regard to their unique function in generating energy and contributing to metabolism within the cell. Furthermore, recent studies suggest that they might have an influence on the innate immune and inflammatory responses, thus affecting antiviral immunity (as example: Zika virus (ZIKV), hepatitis C virus (HCV), dengue virus and SARS-CoV-2 virus) and antibacterial immunity as well (Streptococcus pneumoniae, Mycobacterium leprae and Mycobacterium tuberculosis). Therefore, this chapter aims at bringing a relevant debate about the role of mitochondria and their multifunctional capacity. We intend to discuss the complexity of mitochondrial metabolism, especially during aerobic physical exercises, which causes the modulation of the gene expression of proteins that lead to mitochondrial proliferation and, thus, promote health. In addition, considering the injuries caused by hypoxia, this chapter also stresses the enormous potential of mitochondria to enable the survival of eukaryotic cells by allowing them to turn to aerobic respiration, as shown in previous scientific studies. In conclusion, this chapter points out the importance of mitochondrial biogenesis (both natural and stimulated biogenesis by aerobic exercise) and the benefits this organelle brings to the health, arguing that they go far beyond cellular respiration and oxidative phosphorylation.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae or Mycobacterium lepromatosis. Dermal tissue macrophages and Schwann cells from peripheral nerves are the main host cells for the pathogen. The clinical manifestations of this disease depend basically on the host’s immune response to M. leprae. However, genes relevant to both innate and adaptive immune responses also seem to contribute to leprosy acquisition and to determine its clinical forms. The crucial clinical problem in leprosy is represented by episodes of intense inflammation. They represent a major problem in the course of leprosy, as reactional episodes can be responsible for permanent damage to nerves, causing deformities. Among bacterial pathogens, infection of peripheral nerves is a unique property of M. leprae. The intensity of the inflammatory reaction in response to tissue damage caused by pathogens is strongly associated with mitochondria and their respective mitochondrial DNA, since this organelle and its constituents act as potent ligands for several innate immunity receptors. In this chapter, we will first describe the general context of leprosy and its various clinical forms, diagnosis and treatment, highlighting episodes of acute inflammatory response during this pathology and, finally, we will outline some cellular mechanisms that lead to neurodegenerative consequences in leprosy. The literature partially attributes these to cytokines and, mainly, to TNF-α, as well as to changes in mitochondrial dynamics, especially mitochondrial DNA, when mitochondrial dysfunction seems to be involved in the pathogenesis of neuritis in leprosy.

Tuberculosis (TB) is a contagious infectious disease that is a major cause of morbidity, being one of the top 10 causes of death worldwide, and the leading one from a single infectious agent. Also called “White Plague” in the past, TB is an airborne disease, propagated when multibacillary people spread M. tuberculosis by coughing or sneezing. The disease typically affects the lungs (pulmonary TB), but can also affect other sites (extrapulmonary TB). TB is curable and preventable: about 85% of the people who develop the disease may be successfully treated with a 6-month multidrug regimen. The treatment has the additional benefit of preventing onward transmission. Macrophages are the first host cell to get in contact with M. tuberculosis. They also have important effector functions, regardless of whether the infection evolves to a chronic or latent form. However, M. tuberculosis evades host cell innate defense mechanisms, manipulates organelles and cell metabolism, as well as host cell death pathways. This complex interaction between the host cell and the bacillus determines the outcome of the infection. In this context, mitochondria and mitochondrial DNA (mtDNA) contribute to triggering cell death by necrosis. However, excessive necrosis may lead to tissue damage, which disrupts granulomas and benefits M. tuberculosis transmission. We intend to revisit the major aspects of this intricated and multifaceted interface between the host immune cell and M. tuberculosis and discuss how mitochondria are the crux of the matter

Streptococcus pneumoniae, or pneumococcus, is one of the leading causes of morbidity and mortality associated with lower respiratory infections. Usually, it colonizes asymptomatically the human upper respiratory tract, but it can eventually migrate to other body sites to cause invasive and non-invasive diseases. The polysaccharide capsule (CPS) is the main pneumococcal virulence factor and it is used in the currently available vaccines against this pathogen. However, novel therapeutic and prevention approaches are urgently needed to target emergent non-vaccine serotypes, especially those associated with antimicrobial resistance. Besides CPS, pneumococcus has several other virulence factors that contribute to its pathogenesis, including surface proteins (e.g., CbpA), the pore-forming toxin pneumolysin (PLY), as well as enzymes that produce hydrogen peroxide (H2O2). Here, we describe the pathogenesis of pneumococcal infections as well as host cell molecular signaling, focusing on major molecules responsible for host cell invasion and translocation, and disturbance of mitochondrial function, resulting in mitochondrial DNA (mtDNA) leakage, inflammation and tissue damage. Understanding molecular and immunoinflammatory mechanisms underlying pathogenesis and pathogen-host cell interactions is crucial to developing novel approaches to prevent and treat pneumococcal diseases. 

Zika virus (ZIKV) is a member of the Flavivirus family. ZIKV infection ranges from asymptomatic to a mild disease in adults. However, in 2015, ZIKV infection became a public health emergency in the Americas associated with neurological alterations such as Guillain-Barré syndrome (GBS) in adults and congenital zika syndrome (CZS). By blocking type I IFN interferon signaling pathways, ZIKV evades the immune system and infects cells expressing the T cell immunoglobulin mucin domain-1 (TIM-1) and TAM (Tyro3, AXL, and Mer) receptors, such as neural progenitor cells. Moreover, ZIKV seems to orchestrate a process of astrocytic hypoxia that leads to the production of reactive oxygen species (ROS), mitochondrial DNA (mtDNA) fragmentation, and apoptosis. In recent decades, the active participation of mitochondria in the immuno-inflammatory response has been reported in several pathologies. In this context, mtDNA seems to have an essential role in triggering the innate immune response by activating inflammasomes, activating the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, and also activating toll-like receptors that lead to IFN production and viral clearance. Here, we present an overview of some mechanisms of inflammatory response present in ZIKV infection, which contributes to mitochondrial dysfunction, mtDNA release, and tissue damage. 

 In 2019, a new coronavirus (SARS-CoV-2) was identified in China and had rapidly spread across the world. Its associated disease, coronavirus disease 2019 (COVID-19), has led to millions of deaths in 2020-2021. Studies have been demonstrating that SARS-CoV-2 induces a systemic hyperinflammatory state, which is associated with a decreased cytotoxic capacity and impaired Type I interferon (IFN) response. Moreover, iron dysfunction/hyperferritinemia in association with hyperinflammation leads to oxidative stress and apoptosis. Altogether, these cellular events contribute to COVID-19 severity. In viral infections, systemic and cellular alterations can promote mitochondrial dysfunction. In this regard, dysfunctional mitochondria can trigger the immune response, leading to the release of mitochondrial damage-associated molecular patterns, including mitochondrial DNA (mtDNA) and reactive oxygen species (mtROS). mtDNA is known to promote a beneficial antiviral response; however, sustained nocive stimuli, such as SARS-CoV-2, could turn this response into oxidative stress and exacerbated inflammation leading to tissue injury. In addition, mtDNA can be released into the extracellular space and induce a proinflammatory state in neighboring cells. Here, we highlight the potential role of mtDNA as an important marker of hyperinflammation in the progress of COVID-19. Furthermore, we briefly discuss the role of mtROS and its interactions with the mitochondrial antiviral signaling (MAVS), which can also contribute to COVID-19 immunopathogenesis.