Editorial: Reviews in Microbial Pathogenesis

Svetlana Khaiboullina ¹ Axel Cloeckaert ^2* Daniel Pletzer ³

• ¹ University of Nevada, Reno, Reno, United States
• ² Institut National de recherche pour l’agriculture, l’alimentation et l’environnement (INRAE), Paris, Auvergne, France
• ³ University of Otago, Dunedin, Otago, New Zealand

expresses several surface proteins, including clumping factor B (ClfB), fibronetin-binding protein B (FnBPB), and iron-regulated surface determinant protein A (IsdA), which bind to human loricrin receptor on epithelial cells. This binding facilitates initial adhesion and invasion of host cells (Clarke et al., 2009;da Costa et al., 2022;Mulcahy et al., 2012), particularly on skin and nasal surfaces. Bacterial surface proteins also contribute to immune evasion and persistence (Kim et al., 2010). For example, Clumping factor A(ClfA), collagen adhesin and protein A (SpA) are key factors in the pathogenesis of septic arthritis (Josefsson et al., 2001;Palmqvist et al., 2002;Xu et al., 2004). ClfA is also involved in biofilm formation, which protects S. aureus from phagocytosis (Dastgheyb et al., 2015). The essential role of S. aureus surface proteins in infections make them attractive targets for the development of novel therapeutics. Immunization with IsdA or IsdB has been shown to reduce the virulence of S. aureus (Kim et al., 2010). Additionally, anti-SpA monoclonal antibodies demonstrated therapeutic potential in mouse abscess models (Cheng et al., 2011). Overall, this strongly indicates that targeting specific surface proteins could be a viable strategy for controlling S. aureus infections.Acosta-Espana and Voigt shed light into the differences between entomophthoromycosis and mucormycosis. Fungi, causing entomophthoromycosis and mucormycosis, were initially placed into the class Zygomycetes (Voigt et al., 1999), including Entomophthorales and Mucorales. In 2007, the phylum Zygomycetes was replaced by Mucoromycota and Zoopagomycota (Spatafora et al., 2016). However, the old terms are still used in many publications, creating confusion about fungal species identification. The authors summarize information on Basidiobolales, Entomophthorales, and Mucorales to address this confusing issue and make it clear and easy for clinical researchers to use the updated fungal taxonomy. (Geramizadeh et al., 2015;Kundu & Chakraborty, 2023;Spatafora et al., 2016). Clinical presentations of these infections differ as well. Patients infected withMucorales species have rapid spread with angioinvasion and necrosis (CDC, n.d.). In contrast, the slow progression of clinical symptoms is characteristic of Basidiobolus spp. and Conidiobolus spp. (Raghavan et al., 2020;ScienceDirect, n.d.). The diagnosis is based on epidemiologic, clinical, imaging, histopathologic, microbiologic, and molecular data, followed by the confirmatory report of a fungal culture.A review by Mlynek and Bozue addressed the impact of phase variation and biofilm formation in Francisella tularensis. F. tularensis causes tularemia, a zoonotic disease often transmitted through contact with rabbits (Ellis et al., 2002). There are two primary subspecies: F. tularensis subsp.tularensis (Type A) and F. tularensis subsp. holarctica (Type B), both can be transmitted to humans (Larson et al., 2020). Different species within the Francisella genus exhibit varying capabilities to form biofilms. Subspecies of F. tularensis tend to form less defined structures compared to Francisella novicida (Mahajan et al., 2011;Margolis et al., 2010). These differences are partly due to genetic variations. For example, F. novicida retains a functional cyclic-di-GMP system (cd-GMP), which is absent in F. tularensis (Kingry & Petersen, 2014). The wbt locus in F.tularensis, which contributes to O antigen synthesis, contains genes that are not present in F.novicida (Kingry & Petersen, 2014). GMP stimulates biofilm formation by upregulating genes encoding extracellular polysaccharides (Hickman et al., 2005). Additionally, the O antigen contributes to biofilm formation in F. tularensis isolates (Champion et al., 2019). Biofilms enhance bacterial persistence by protecting against host defenses and antibiotic treatment. Notably, biofilm formation has been shown to reduce susceptibility of F. tularensis to ciprofloxacin (Siebert et al., 2020), further complicating treatment efforts.The role of Francisella peptidoglycan biosynthesis enzymes in morphology, pathogenesis and treatment of infection is discussed in the review by Bachert and Bozue. The bacterial cell wall is constantly remodelling in response to environmental changes and cell division. Peptidoglycan (PG) remodelling is a coordinated process involving several enzymes. PG biosynthesis begins with the formation of a lipid II precursor (Egan et al., 2020). The precursor is subsequently polymerized with penicillin-binding proteins (PBPs). Many organisms encode multiple PG enzymes with redundant function (Lee et al., 2017;van Heijenoort, 2011). Interestingly, this is not a characteristic of F. tularensis (Kijek et al., 2019). There are currently five known carboxypeptidases and two lytic transglycosylases known in Francisella. They all have distinct roles in cell morphology (Spidlova et al., 2018;Zellner et al., 2021) and contribute to the immunomodulating activity of this bacterium (Nakamura et al., 2021). This suggests that PG enzymes could be used as a therapeutic target specifically against this organism.Approaches for identifying bacterial effector kinases are summarized in the review by Louis et al.Many pathogens encode proteins with sequence homology to eukaryotic kinase domains (Anderson et al., 2015;Moss et al., 2019;Navarro et al., 2007). Some of these bacterial kinases can phosphorylate host cell proteins to manipulate signaling pathways, thereby promoting bacterial replication and survival within the host (Park et al., 2019;Tegtmeyer et al., 2017). However, understanding the role of these kinases in the pathogenesis of bacterial disease is limited, primarily due to insufficient knowledge of their target host proteins. Improved identification of host targets for bacterial kinases could pave the way for the development of novel antimicrobial therapeutics that disrupt these critical interactions.Manipulation of host signaling pathways by Neisseria gonorrhoeae is discussed by Walker et al.The mucosal epithelium serves as the primary portal of entry for N. gonorrhoeae (Quillin & Seifert, 2018). During colonization, bacterial pili facilitate cell-to-cell contact with the epithelium, while Opa proteins further promote adherence. Gonococci pili bind to several host receptors, including α1β1 and α2β1 integrins in the male urethral epithelium (Edwards & Apicella, 2005). In contrast, gonococcal pili can also bind to the complement receptors, CD46 and CR3, as well as the I-domain containing integrin receptors (Edwards et al., 2001). The interaction between microbial Opa protein and the CEACAM family of receptors on neutrophils contributes to the clinical manifestation of gonococcal infection (Sarantis & Gray-Owen, 2012). The CEACAM-Opa interaction promotes the colonization of cervical epithelial cells by suppressing exfoliation (Yu et al., 2019). Furthermore, CEACAM-Opa inhibits Th1/Th2 lymphocyte responses while promoting a pro-inflammatory Th17 lymphocyte phenotype (Feinen et al., 2010;Y. Liu et al., 2012). Another key gonococcal protein, PorB, increases calcium influx, which is required to reduce lysosome counts in infected cells (Hopper et al., 2000). PorB also reprograms macrophages (Mosleh et al., 1998) to create a more favorable environment for survival. Additionally, PorB can bind to soluble C4b-binding protein (C4BP) and factor H of complement (Ram et al., 1998(Ram et al., , 2001)), aiding immune evasion. Understanding the mechanisms employed by N. gonorrhoeae to evade immune clearance and promote intracellular replication is essential for the development of vaccines and therapeutics.The importance of interaction between host and microbial neuraminidases (NA) in the pathogenesis of viral and bacterial co-infection of respiratory epithelium is discussed by Escuret and Terrier. Pathogens infecting epithelial cells of the respiratory tract such as influenza viruses use NA and hemagglutinin (HA) to enter the cell. Bacteria can also express NA for adherence and invasion of epithelial cells (Vimr & Lichtensteiger, 2002). Intriguingly, during viral-bacterial coinfections, viral NA can remove sialic acids that typically mask bacterial adhesion receptors, thereby facilitating bacterial colonization (PELTOLA & MCCULLERS, 2004). This synergistic effect enhances the severity of respiratory infections (Wren et al., 2017). Given the pivotal role of NA in viral and bacterial interactions, they present attractive targets for developing preventive and therapeutic strategies aimed at mitigating co-infection severity.Jin et al. discussed the advancements in the understanding of mechanisms of Bartonella pathogenesis. Endothelial cells are the primary target for Bartonella species (Deng et al., 2012).The bacterium uses α-enolase or phosphopyruvate hydratase to activate plasmin and promote extracellular matrix degradation (Díaz-Ramos et al., 2012). The Bartonella BadA protein can activate hypoxia-inducible factor-1 and secrete pro-angiogenic cytokines (Kempf et al., 2001(Kempf et al., , 2005)). It can also provide resistance to complement killing (Deng et al., 2012). BadA and Vomp proteins also facilitate immune evasion by antigen variations (Linke et al., 2006). To evade the immune repose, Bartonella produces LPS, an antagonist of the TLR4 receptor (Malgorzata-Miller et al., 2016). Still, many aspects of Bartonella's pathogenesis remain unknown, requiring the development of novel in vivo and in vitro methods.Recent data on pathogens causing sepsis are summarized in the review by Gatica et al. A diverse group of pathogens that belong to the normal microflora (Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pyogenes) can cause sepsis (Gouel-Cheron et al., 2022). Sepsis risk increases with age, compromised immunocompetence and comorbidities. Also, each microbe has a unique set of virulence factors facilitating adhesion, penetration and replication. Therefore, approaches for diagnosis and treatment will differ for each type of sepsis. The traditional use of antibiotics led to the development of drug-resistant strains, making therapeutic options limited. Therefore, searching for new approaches for diagnosing and treating sepsis remains a pressing medical issue.In the review by Ayesha et al. the role of Legionella pneumophila outer membrane vesicles (OMVs) in interaction with the host is discussed. L. pneumophila secretes OMVs containing proteins, toxins, nucleic acids and antibiotic-resistance enzymes (Flesher, 1979). OMV cargo delivered to eukaryotic cells can inhibit innate protection against bacteria. For example, it was shown that proteins delivered by OMVs can inhibit the fusion of legionella-containing phagosomes and lysosomes (Fernandez-Moreira et al., 2006). Also, OMVs can inhibit the production of pro-inflammatory cytokines by macrophages (Jung et al., 2016). The ability of OMVs to deliver the cargo could be used to develop vaccines and deliver drugs.The role of infection in Kawasaki vasculitis is discussed in the review by Wang et al.Environmental factors were suggested to play a role in the disease pathogenesis (Chang et al., 2020). However, the seasonal nature of outbreaks suggests an infectious aetiology of Kawasaki vasculitis (Valtuille et al., 2023). Multiple DNA and RNA viruses and bacterial pathogens were suggested as causing Kawasaki vasculitis (Guo et al., 2022;Huang et al., 2020;Kafetzis et al., 2001;Xiao et al., 2020). Having many microbes linked to Kawasaki vasculitis could indicate that the disease is multifactorial, where multiple factors contribute to the disease pathogenesis.The role of lipolytic enzymes in the pathogenesis of Mycobacterium tuberculosis is discussed in the review by Lin et al. There are four types of lipolytic enzymes in M. tuberculosis (Mtb) based on specificity to a substrate (Dedieu et al., 2013;Delorme et al., 2012) The first class contains lipases hydrolyzing water-insoluble long-chain carboxylesters like long-chain triglycerides (TAG). Esterases are in the second group, which hydrolyze small water-soluble carboxylesters.The third group includes phospholipases. The last four groups contain cutinases, which digest carboxylesters. Lipases digest lipids in the extracellular matrix, promoting Mtb tissue penetration (Nazarova et al., 2017). Also, Mtb lipases digest lipids to release energy and survive inside the cells (Kumari et al., 2020). Mtb lipases could be used as a disease biomarker (Low et al., 2009) or could be a target for novel therapeutics (West et al., 2011).The interaction between microflora and cervical cancer progression is discussed by Amaris et al.Cervical cancer is ranked as the most common cancer in women (Arbyn et al., 2020).Fusobacterium spp., Peptostreptococcus spp., Campylobacter spp., and Haemophilus spp., as potential biomarkers for cervical cancer progression (He et al., 2022;Wu et al., 2021;Zhou et al., 2022). Additionally, Alloscardovia spp., Eubacterium spp., and Mycoplasma spp. were identified in HPV-positive cervical cancer (Gao et al., 2013), while Methylobacterium spp. were more often detected in HPV-negative carcinomas.Animal models of Klebsiella pneumonia infection of the mucosa are summarized by Assoni et al.Multiple factors should be considered when selecting an animal model: site of infection, type of immune response and susceptibility of an animal. Mice and rats were the most used to study K.pneumonia respiratory tract infection (Ferreira et al., 2019;van der Weide et al., 2020). A rabbit model was used to study empyema caused by K. pneumonia (Shohet et al., 1987). More recently, cynomolgus macaques were used to study the pathogenesis and immune response to K. pneumonia (J.-Y. Liu et al., 2022). This model provides an inside look at the immune response to this microbe.The Zebrafish model was used to study neutrophil and macrophage reaction to K. pneumonia (Zhang et al., 2019). K. pneumonia can colonize different niches, which makes it challenging to select an appropriate animal model. Careful considerations should be taken before selecting a model to study K. pneumonia infection.In conclusion, this Research Topic provides a collection of reviews covering pathogenic mechanisms of some important microbial pathogens of the section Infectious Agents and Disease. This collection will be of interest for researchers, healthcare providers and infection control officials.