# Editorial: Reviews in microbial pathogenesis

Axel Cloeckaert, Daniel Pletzer, Svetlana Khaiboullina

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Axel Cloeckaert, Daniel Pletzer, Svetlana Khaiboullina. Editorial: Reviews in microbial pathogenesis. Frontiers in Microbiology, 2025, 16, pp.1568840. 10.3389/fmicb.2025.1568840. hal-05033108

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EDITED AND REVIEWED BY
Paul David Cotter,
Seqbiome Ltd, Ireland

*CORRESPONDENCE

Axel Cloeckaert

axel.cloeckaert@inrae.fr

RECEIVED 30 January 2025

ACCEPTED 13 February 2025

PUBLISHED 28 February 2025

CITATION

Cloeckaert A, Pletzer D and Khaiboullina S (2025) Editorial: Reviews in microbial pathogenesis. *Front. Microbiol.* 16:1568840. doi: 10.3389/fmicb.2025.1568840

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© 2025 Cloeckaert, Pletzer and Khaiboullina. This is an open-access article distributed under the terms of the [Creative Commons Attribution License (CC BY)](https://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Editorial: Reviews in microbial pathogenesis

Axel Cloeckaert¹*, Daniel Pletzer² and Svetlana Khaiboullina³

¹INRAE, Université de Tours, UMR, ISP, Nouzilly, France, ²Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand, ³Department of Microbiology and Immunology, University of Nevada, Reno, NV, United States

KEYWORDS

microbiology, review, infectious disease, pathogens, microbial pathogenesis, virulence

Editorial on the Research Topic

Reviews in microbial pathogenesis

Microbiology is a fast-growing research field. The rapid expansion of this field is driven by ongoing discoveries of emerging pathogens, microbial adaptation, resistance mechanisms and technological advancements. While these trends will likely continue to drive new discoveries and novel solutions for infectious diseases, the overwhelming volume of research publications makes it difficult for scientists to keep pace with the latest findings. Additionally, access to cutting-edge research can be limited by paywalls, creating barriers for both early-career researchers and those in resource-limited settings.

The present Research Topic, focusing on reviews in microbial pathogenesis, includes 16 publications (15 peer-reviewed articles and 1 erratum), including 72 authors, to address these challenges. By providing open-access, comprehensive reviews and accessible summaries of recent findings, this Research Topic offers a valuable platform for the researchers to navigate key advancements in the field of microbiology, emphasizing important directions for future research and offer insights into emerging trends and methodologies.

The review by *Mohammad et al.* addressed the role of lipoproteins (Lpps) in the pathogenesis of *Staphylococcus aureus*. *S. aureus* produces Lpps that contribute to metabolism, are essential for the survival of bacteria and are important for tissue invasion. Additionally, they are capable of affecting disease pathogenesis by modulating the immune response (*Mohammad et al.*, 2020; *Nguyen and Götz*, 2016) via binding to Toll-Like Receptors 2 (TLR2), leading to activation of innate immune responses (*Hashimoto et al.*, 2006). Binding of these molecules to TLR2 causes rapid migration of innate immune cells, including monocytes/macrophages and neutrophils (*Mohammad et al.*, 2019, 2021). Also, Lpps can stimulate interferon γ producing T cells (*Saito and Quadery*, 2018), although there is limited effect on B cell activation (*Mohammad et al.*, 2019). The *in vitro* and *in vivo* effects of Lpps are believed to be mediated by interaction with TLR2-dependent neutrophil recruitment (*Mohammad et al.*, 2019). It was demonstrated that neutrophils and macrophage recruitment is facilitated by the release of chemokines such as MIP-2, KC, MCP-1 and MPO (*Mohammad et al.*, 2021). The role of TLR2 in the pathogenesis of Lpps-induced pathology is also supported by the TLR2-knockout mouse model (*Schmaler et al.*, 2009).

In another review, Schwermann and Winstel summarize the functional diversity of *Staphylococcus* surface proteins, which play a crucial role in host interaction and pathogenesis. *Staphylococcus* 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-España 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. The authors state that current taxonomy identifies the classes Mucoromycota (order Mucorales), Zoopagomycota (order Entomophthorales [Conidiobolus spp.]) and Basidiobolales (Basidiobolus spp.). Instead of the term "zygomycosis", more defined terms should be used, such as: 1. Infection with Mucorales should be referred to as mucormycosis; 2. Infection with Basidiobolus spp. as basidiobolomycosis; 3. Conidiobolus spp. as conidiobolomycosis. These fungal infections have differences in pathogenesis as mucormycosis is diagnosed primarily in patients with impaired cellular immunity [Center for Disease and Prevention (CDC), n.d.], while basidiobolomycosis and conidiobolomycosis occur in immunocompetent patients (Geramizadeh et al., 2015; Kundu and Chakraborty, 2023; Spatafora et al., 2016). Clinical presentations of these infections differ as well. Patients infected with Mucorales species have rapid spread with angioinvasion and necrosis [Center for Disease and Prevention (CDC), n.d.]. In contrast, the slow progression of clinical symptoms is characteristic of Basidiobolus spp. and Conidiobolus spp. (Raghavan et al., 2020). 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 (c-di-GMP), which is absent in *F. tularensis* (Kingry and
Petersen, 2014). The *wbt* locus in *F. tularensis*, which contributes
to O antigen synthesis, contains genes that are not present
in *F. novicida* (Kingry and 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 remodeling in response to environmental changes and
cell division. Peptidoglycan (PG) remodeling 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 carboxypeptidases and two
lytic transglycosylases known in Francisella (Sauvage et al., 2008).
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 and 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 and 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 and 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; 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, 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 and Lichtensteiger, 2002). Intriguingly, during viral-bacterial co-infections, viral NA can remove sialic acids that typically mask bacterial adhesion receptors, thereby facilitating bacterial colonization (Peltola and 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 phosphoryruvate 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, 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 et al., 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 etiology 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* (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 Research Topic will be of interest for researchers, healthcare providers and infection control officials.

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## Author contributions

AC: Writing – original draft, Writing – review & editing. DP: Writing – original draft, Writing – review & editing. SK: Writing – original draft, Writing – review & editing.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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