Innate Immune Recognition of Mycobacterium tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a major health problem, with 10 million new cases diagnosed each year. Innate immunity plays an important role in the host defense against M. tuberculosis, and the first step in this process is recognition of MTB by cells of the innate immune system. Several classes of pattern recognition receptors (PPRs) are involved in the recognition of M. tuberculosis, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs). Among the TLR family, TLR2, TLR4, and TLR9 and their adaptor molecule MyD88 play the most prominent roles in the initiation of the immune response against tuberculosis. In addition to TLRs, other PRRs such as NOD2, Dectin-1, Mannose receptor, and DC-SIGN are also involved in the recognition of M. tuberculosis. Human epidemiological studies revealed that genetic variation in genes encoding for PRRs and downstream signaling products influence disease susceptibility, severity, and outcome. More insight into PRRs and the recognition of mycobacteria, combined with immunogenetic studies in TB patients, does not only lead to a better understanding of the pathogenesis of tuberculosis but also may contribute to the design of novel immunotherapeutic strategies

Innate Immune Recognition of mtDNA—An Undercover Signal?

In addition to their roles in cellular metabolism and apoptosis, mitochondria function as signaling platforms in the innate immune response. In Nature, West et al. (2015) demonstrate that mitochondrial stress triggers a type I interferon response and confers viral resistance via release of mtDNA and activation of the cGAS–STING pathway

Innate Immune Recognition of Candida Albicans in Zebrafish

Candida albicans is an opportunistic fungal pathogen that has the capability to switch from commensal to pathogen in immunocompromised individuals. Recognition of pathogens, like C. albicans, during infection is poorly characterized primarily due to the difficulties in visualizing the host/pathogen interaction without killing the host. Transparent animal hosts, such as Danio rerio (zebrafish), enable imaging of pathogen recognition while maintaining host viability. For pathogen recognition, zebrafish likely use immune receptors similar to mammalian receptors including C-type lectin receptors. Human C-type lectin receptors have already been shown to be crucial in recognition of fungal pathogens like C. albicans, and our goal is to identify and characterize cognate receptors crucial for fungal recognition in zebrafish. Here, I show how I purified fusion proteins of recently identified receptors and began characterizing the binding of these receptors to Candida albicans. Determining the specificity of these receptors may enhance our understanding of fungal recognition in the zebrafish host and the evolution of vertebrate immune receptor specificity. In addition, receptors that bind to C. albicans could be used as a diagnostic for C. albicans infection in patients

Fungal Surface and Innate Immune Recognition of Filamentous Fungi

The innate immune system performs specific detection of molecules from infectious agents through pattern recognition receptors. This recognition triggers inflammatory responses and activation of microbicidal mechanisms by leukocytes. Infections caused by filamentous fungi have increased in incidence and represent an important cause of mortality and morbidity especially in individuals with immunosuppression. This review will discuss the innate immune recognition of filamentous fungi molecules and its importance to infection control and disease

Innate Immune Recognition of Yersinia pseudotuberculosis Type III Secretion

Specialized protein translocation systems are used by many bacterial pathogens to deliver effector proteins into host cells that interfere with normal cellular functions. How the host immune system recognizes and responds to this intrusive event is not understood. To address these questions, we determined the mammalian cellular response to the virulence-associated type III secretion system (T3SS) of the human pathogen Yersinia pseudotuberculosis. We found that macrophages devoid of Toll-like receptor (TLR) signaling regulate expression of 266 genes following recognition of the Y. pseudotuberculosis T3SS. This analysis revealed two temporally distinct responses that could be separated into activation of NFκB- and type I IFN-regulated genes. Extracellular bacteria were capable of triggering these signaling events, as inhibition of bacterial uptake had no effect on the ensuing innate immune response. The cytosolic peptidoglycan sensors Nod1 and Nod2 and the inflammasome component caspase-1 were not involved in NFκB activation following recognition of the Y. pseudotuberculosis T3SS. However, caspase-1 was required for secretion of the inflammatory cytokine IL-1β in response to T3SS-positive Y. pseudotuberculosis. In order to characterize the bacterial requirements for induction of this novel TLR-, Nod1/2-, and caspase-1-independent response, we used Y. pseudotuberculosis strains lacking specific components of the T3SS. Formation of a functional T3SS pore was required, as bacteria expressing a secretion needle, but lacking the pore-forming proteins YopB or YopD, did not trigger these signaling events. However, nonspecific membrane disruption could not recapitulate the NFκB signaling triggered by Y. pseudotuberculosis expressing a functional T3SS pore. Although host cell recognition of the T3SS did not require known translocated substrates, the ensuing response could be modulated by effectors such as YopJ and YopT, as YopT amplified the response, while YopJ dampened it. Collectively, these data suggest that combined recognition of the T3SS pore and YopBD-mediated delivery of immune activating ligands into the host cytosol informs the host cell of pathogenic challenge. This leads to a unique, multifactorial response distinct from the canonical immune response to a bacterium lacking a T3SS

Innate immune recognition of the microbiota promotes host-microbial symbiosis

Pattern-recognition receptors (PRRs) are traditionally known to sense microbial molecules during infection to initiate inflammatory responses. However, ligands for PRRs are not exclusive to pathogens and are abundantly produced by the resident microbiota during normal colonization. Mechanism(s) that underlie this paradox have remained unclear. Recent studies reveal that gut bacterial ligands from the microbiota signal through PRRs to promote development of host tissue and the immune system, and protection from disease. Evidence from both invertebrate and vertebrate models reveals that innate immune receptors are required to promote long-term colonization by the microbiota. This emerging perspective challenges current models in immunology and suggests that PRRs may have evolved, in part, to mediate the bidirectional cross-talk between microbial symbionts and their hosts

INNATE IMMUNE RECOGNITION, REGULATION AND EVASION

Vertebrates are constantly threatened by the invasion of microorganisms. The innate immune system is the first line of host defense and utilizes pattern-recognition receptors (PRRs) to sense microbial components, known as pathogen-associated molecular patterns (PAMPs). These PRRs also recognize molecules released by the damaged host tissue, known as damage-associated molecular patterns (DAMPs). Innate immune sensing of PAMP/DAMP will activate intracellular signaling cascade and initiate a rapid immune response. In addition, the innate immune response must be under tight control for preventing inadvertent immunopathology and maintaining immune homeostasis. On the other side, the pathogen has evolved adaptations that can blunt innate immune signaling and promotes immune evasion. This dissertation has four topics, all related to innate immunity and disease outcomes. First, we found that a new DAMP sensing signal presented by platelet activation factor (PAF) activation of the NLRP3 inflammasome; Second, we defined a new PRR by demonstrating that NLRC3 is an authentic DNA binding receptor that recognizes Herpes simplex virus DNA. Third, we found a new immune regulation mechanism where TRAF3IP3 inhibits cytosolic RNA induced type I interferon signaling. Finally, we describe a new immune evasion mechanism where hepatitis A virus protease induces proteolysis of GSDME and abolishes virus induced pyroptosis. These findings reveal novel innate immune sensing signaling and regulation mechanism as well as the counteraction of pathogen against host defense. This will advance our understanding the pathogenesis of infectious, inflammatory and autoimmune diseases, and will also provide the scientific rationale and precision target for developing novel therapies against these diseases.Doctor of Philosoph

Innate Immune Recognition and Inflammasome Activation in Listeria Monocytogenes Infection

Listeria monocytogenes is an intracellular, Gram-positive bacterium that can cause life-threatening illness especially in immunocompromised individuals and newborns. The pathogen propagates within the cytosol of various host cells after escaping from the phagosomal compartment depending on the cytolysin listeriolysin O. While L. monocytogenes can manipulate the endocytic and many host-cell signaling cascades to its advantage, host cells are however capable of detecting Listeria infection at different cellular compartments by expressing innate immune receptors that trigger antibacterial defense pathways. These receptors include the Toll-like receptors, NOD-like receptors (NLRs), and cytosolic DNA sensors. Some NLRs as well as the DNA sensor AIM2 form multiprotein complexes called inflammasomes. Inflammasomes regulate caspase-1-dependent production of the key inflammatory cytokines IL-1β and IL-18 as well as pyroptotic cell death in L. monocytogenes-infected cells. This review describes the current knowledge about innate immune sensing and inflammasome activation in Listeria infection

Host cell-intrinsic innate immune recognition of SARS-CoV-2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged at the end of 2019 and caused the pandemic of coronavirus disease 2019 (COVID-19). Basic and clinical investigations indicate that severe forms of COVID-19 are due in part to dysregulated immune responses to virus infection. The innate immune system is the first line of host defense against most virus infections, with pathogen recognition receptors detecting SARS-CoV-2 RNA and protein components and initiating pro-inflammatory and antiviral responses. Notwithstanding this response, SARS-CoV-2 proteins evade, inhibit, and skew innate immune signaling early in infection. In this review, we highlight the components of cell-based recognition of SARS-CoV-2 infection and the mechanisms employed by the virus to modulate these innate immune host defense pathways