pathogens Review Interplay between ESKAPE Pathogens and Immunity in Skin Infections: An Overview of the Major Determinants of Virulence and Antibiotic Resistance Gustavo Henrique Rodrigues Vale de Macedo 1,2 , Gabrielle Damasceno Evangelista Costa 1,2, Elane Rodrigues Oliveira 2, Glauciane Viera Damasceno 2, Juliana Silva Pereira Mendonça 1,2, Lucas dos Santos Silva 2, Vitor Lopes Chagas 2, José Manuel Noguera Bazán 3, Amanda Silva dos Santos Aliança 4, Rita de Cássia Mendonça de Miranda 1,5 , Adrielle Zagmignan 2, Andrea de Souza Monteiro 1,6 and Luís Cláudio Nascimento da Silva 1,2,3,* 1 Programa de Pós-graduação em Biologia Microbiana, Universidade CEUMA, 65075-120 São Luís, Brazil; [email protected] (G.H.R.V.d.M.); [email protected] (G.D.E.C.); [email protected] (J.S.P.M.); [email protected] (R.d.C.M.d.M.); [email protected] (A.d.S.M.) 2 Laboratório de Patogenicidade Microbiana, Universidade CEUMA, 65075-120 São Luís, Brazil; [email protected] (E.R.O.); [email protected] (G.V.D.); [email protected] (L.d.S.S.); [email protected] (V.L.C.); [email protected] (A.Z.) 3 Programa de Pós-graduação em Odontologia, Universidade CEUMA, 65075-120 São Luís, Brazil; [email protected] 4 Programa de Pós-graduação em Gestão de Programas e Serviços de Saúde, Universidade CEUMA, 65075-120 São Luís, Brazil; [email protected] Citation: Vale de Macedo, G.H.R.; 5 Programa de Pós-graduação em Meio Ambiente, Universidade CEUMA, 65075-120 São Luís, Brazil Costa, G.D.E.; Oliveira, E.R.; 6 Laboratório de Microbiologia Aplicada, Universidade CEUMA, 65075-120 São Luís, Brazil Damasceno, G.V.; Mendonça, J.S.P.; * Correspondence: [email protected] Silva, L.d.S.; Chagas, V.L.; Bazán, J.M.N.; Aliança, A.S.d.S.; Miranda, Abstract: The skin is the largest organ in the human body, acting as a physical and immunological R.d.C.M.d.; et al. Interplay between barrier against pathogenic microorganisms. The cutaneous lesions constitute a gateway for microbial ESKAPE Pathogens and Immunity in contamination that can lead to chronic wounds and other invasive infections. Chronic wounds are Skin Infections: An Overview of the considered as serious public health problems due the related social, psychological and economic Major Determinants of Virulence and Antibiotic Resistance. Pathogens 2021, consequences. The group of bacteria known as ESKAPE (Enterococcus faecium, Staphylococcus aureus, 10, 148. https://doi.org/10.3390/ Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter sp.) are among pathogens10020148 the most prevalent bacteria in cutaneous infections. These pathogens have a high level of incidence in hospital environments and several strains present phenotypes of multidrug resistance. In this Academic Editor: Catherine Wakeman review, we discuss some important aspects of skin immunology and the involvement of ESKAPE in Received: 11 January 2021 wound infections. First, we introduce some fundamental aspects of skin physiology and immunology Accepted: 27 January 2021 related to cutaneous infections. Following this, the major virulence factors involved in colonization Published: 2 February 2021 and tissue damage are highlighted, as well as the most frequently detected antimicrobial resistance genes. ESKAPE pathogens express several virulence determinants that overcome the skin’s physical Publisher’s Note: MDPI stays neutral and immunological barriers, enabling them to cause severe wound infections. The high ability these with regard to jurisdictional claims in bacteria to acquire resistance is alarming, particularly in the hospital settings where immunocompro- published maps and institutional affil- mised individuals are exposed to these pathogens. Knowledge about the virulence and resistance iations. markers of these species is important in order to develop new strategies to detect and treat their associated infections. Keywords: skin infections; chronic wounds; hypervirulent phenotypes; multidrug resistance Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Attribution (CC BY) license (https:// Skin wounds are considered a serious public health problem, resulting in social, creativecommons.org/licenses/by/ psychological and economic consequences [1,2]. Since wounds impair the anatomical 4.0/). continuity of the skin, they substantially increase the risk of microbial contamination, Pathogens 2021, 10, 148. https://doi.org/10.3390/pathogens10020148 https://www.mdpi.com/journal/pathogens Pathogens 2021, 10, x FOR PEER REVIEW 2 of 36 Pathogens 2021, 10, 148 2 of 34 Skin wounds are considered a serious public health problem, resulting in social, psy- as thechological lesions and constitute economica conseq gatewayuences for [1,2]. microorganisms Since wounds [impair3–5]. Inthe fact,anatomical wounds conti- induced bynuity prolonged of the hospitalizationsskin, they substantially and surgicalincrease interventionsthe risk of microbial have contamination, a strong association as the with healthcare-relatedlesions constitute infectionsa gateway [for6,7 ].microorganisms [3–5]. In fact, wounds induced by pro- longedOnce thehospitalizations tissue integrity and is surgical impaired, interventions a cascadeof have biochemical a strong reactions, association known with as the healinghealthcare-related process, is activated infections to[6,7]. repair the damage [8–10]. The healing pathway consists of distinctOnce and overlappingthe tissue integrity phases is impaired, comprising a cascade homeostasis, of biochemical inflammation, reactions, proliferation, known as re- epithelializationthe healing process, and tissueis activated remodeling to repair [the9,11 damage]. The presence[8–10]. The of healing pathogenic pathway microorganisms consists of distinct and overlapping phases comprising homeostasis, inflammation, proliferation, extends the inflammation period which is characterized by the exacerbated release of re-epithelialization and tissue remodeling [9,11]. The presence of pathogenic microorgan- inflammatoryisms extends mediators the inflammation in response period to which bacterial is characterized persistence, by closely the exacerbated associated release to biofilm formationof inflammatory [12–14]. mediators in response to bacterial persistence, closely associated to bio- filmMoreover, formation the [12–14]. cytotoxic action of bacterial virulence determinants results in cell dam- age andMoreover, this may the amplify cytotoxic the action inflammation of bacterial [15 virulence–18]. The determinants prolongation results of the in cell inflammatory dam- phaseage and results this inmay an amplify impairment the inflammation of the healing [15–18]. process The prolongation [12,14,19]. of In the this inflammatory sense, microbial infectionsphase results are highlighted in an impairment as the of most the healing important process causes [12,14,19]. of chronic In this wounds sense, microbial and are usu- allyinfections associated are withhighlighted biofilm as formation,the most import whichant arecauses notoriously of chronic wounds recalcitrant and are to conventionalusually antibioticsassociated [20 with,21 ].biofilm The class formation, of microorganisms which are notoriously known recalcitrant as ESKAPE to (conventionalEnterococcus an- faecium, Staphylococcustibiotics [20,21]. aureus The, Klebsiella class of microorganisms pneumoniae, Acinetobacter known as ESKAPE baumannii (Enterococcus, Pseudomonas faecium aeruginosa, andStaphylococcusEnterobacter sp.)aureus are, Klebsiella among thepneumoniae most prevalent, Acinetobacter bacteria baumannii in cutaneous, Pseudomonas infections aeru- [22–24]. ginosa and Enterobacter sp.) are among the most prevalent bacteria in cutaneous infections The dynamics of bacterial infection of the skin are illustrated in Figure1. [22–24]. The dynamics of bacterial infection of the skin are illustrated in Figure 1. Figure 1. A schematic view of bacterialFigure 1. A skin schematic infection, view derived of bacterial from skin a loss infection, in epidermis derived integrity.from a loss (1) in epidermis An injury integrity. provokes a skin lesion that constitutes a gateway(1) An injury for microbial provokes a contamination. skin lesion that constitutes (2) Bacteria a gateway colonize for the microbial skin and contamination. produce a biofilm.(2) (3) Bacteria secrete toxins that extendBacteria thecolonize tissue the degradation, skin and produce reaching a biofilm. dermis (3) Bacteria layer. (4) secret Residente toxins immune that extend cells the recognize tissue degradation, reaching dermis layer. (4) Resident immune cells recognize the bacteria and secrete the bacteria and secrete immune mediators to neutralize the pathogens and recruit other immune cells. (5) Cell debris immune mediators to neutralize the pathogens and recruit other immune cells. (5) Cell debris (damage-associated molecular patterns(damage-associated (DAMPS) molecular and lipid patterns mediators) (DAMPS) activate and immune lipid mediators) cells and activate serve asimmune chemoattractors. cells and (6) Blood leukocytes are recruitedserve to as combat chemoattractors. the pathogens. (6) Blood (7) Effectorleukocytes substances are recruited released to combat by immunethe pathogens. cells also(7) Effector promote tissue damage and amplify thesubstances inflammation. released by immune