Host-Pathogen Interactions in Acinetobacter baumannii Infections: Mechanisms of Immune Evasion and Potential Therapeutic Targets

Abstract

The book chapter titled “Host–Pathogen Interactions in Acinetobacter baumannii Infections: Mechanisms of Immune Evasion and Potential Therapeutic Targets” provides an in-depth exploration of the complex interplay between A. baumannii, a notorious multidrug-resistant pathogen, and the host immune system. The chapter will focus on elucidating the mechanisms employed by A. baumannii to evade and subvert the immune response, leading to persistent and challenging infections. It will highlight key aspects of the host immune system, including innate and adaptive immunity, pattern-recognition receptors, and immune cell responses, in the context of A. baumannii infections. Additionally, the chapter discusses the virulence factors and strategies employed by A. baumannii to establish infection, such as biofilm formation and quorum sensing. Importantly, the chapter will explore potential therapeutic targets for combating A. baumannii infections, including novel antimicrobial agents, immunotherapies, and host-directed therapies. The comprehensive analysis of host–pathogen interactions and identification of therapeutic strategies presented in this chapter contribute to our understanding of A. baumannii infections and pave the way for future research directions and healthcare interventions in combating this formidable pathogen.

1. Introduction

1.1 Background and significance of A. baumannii infections

A. baumannii has gained notoriety as an emerging nosocomial pathogen, characterized by its rapid development of drug resistance and its affinity for adhering to abiotic surfaces, including medical equipment [1]. This unique ability contributes to the widespread dissemination of the bacterium and presents a formidable challenge in controlling A. baumannii infections, particularly ventilator-associated pneumonia in clinical settings [2]. A comprehensive understanding of the intricate host–pathogen interactions during A. baumannii infections is needed to combat this elusive pathogen effectively.

The chapter delves into the array of virulence factors employed by A. baumannii that are recognized by host innate pattern-recognition receptors. Activation of downstream inflammasomes triggers inflammatory responses, and innate immune effectors are recruited to counter A. baumannii infection. This detailed analysis reveals the tug-of-war between the pathogen’s virulence factors and the host’s immune surveillance, highlighting a complex dance determining the course of the disease.

A. baumannii strategically regulates the expression of various virulence factors to counteract host immune attacks [1, 2]. The chapter illuminates these evasion strategies, providing insights into how the bacterium manipulates the immune landscape. Furthermore, the discussion extends to potential therapeutic targets to combat A. baumannii infections. Novel antimicrobial agents, immunotherapies, and host-directed therapies are evaluated for their potential to disrupt the delicate balance of host–pathogen interactions.

The comprehensive analysis presented in this chapter significantly contributes to our understanding of A. baumannii infections and paves the way for future research avenues and healthcare interventions. By unraveling the intricate mechanisms of immune evasion and identifying potential therapeutic targets, this chapter empowers the scientific community to combat the challenges posed by A. baumannii and devise strategies that promise to improve patient outcomes and address this urgent global health concern.

1.2 Objectives and scope of the book chapter

The primary objective of the book chapter is to provide a comprehensive exploration of the intricate interplay between the multidrug-resistant pathogen A. baumannii and the host immune system. The chapter aims to elucidate the mechanisms underlying A. baumannii’s ability to evade and subvert the host immune response, thereby establishing persistent and challenging infections. By delving into the complex interactions between the pathogen and the immune system, the chapter contributes to a deeper understanding of A. baumannii infections.

The scope of the chapter encompasses various facets of host–pathogen interactions, focusing on innate and adaptive immunity. It covers key components such as pattern-recognition receptors, immune cell responses, and the role of virulence factors in evading immune surveillance. Additionally, the chapter explores the virulence strategies employed by A. baumannii, including biofilm formation and quorum sensing. Importantly, the chapter goes beyond elucidating the immune evasion mechanisms and examines potential therapeutic targets for combating A. baumannii infections. In addition, it includes a detailed discussion of novel antimicrobial agents, immunotherapies, and host-directed therapies. Overall, the chapter aims to provide a comprehensive analysis that contributes to our understanding of A. baumannii infections and paves the way for future research directions and healthcare interventions.

2. Overview of A. baumannii

2.1 Taxonomy and classification

A. baumannii belongs to the domain bacteria, phylum Pseudomonadota, class Gammaproteobacteria, order Pseudomonadales, and family Moraxellaceae within the genus Acinetobacter [1]. The genus includes various species, among which the A. baumannii complex is of particular clinical relevance. This complex comprises A. baumannii, Acinetobacter nosocomialis, A. pitii, and Acinetobacter calcoaceticus [2]. Among these, A. baumannii is the most clinically significant species within this complex, responsible for various hospital-acquired infections [1].

The A. calcoaceticus-A. baumannii complex (ACB complex) is a group of closely related bacterial species within the genus Acinetobacter. This complex comprises several species that share genetic similarities and often pose challenges for accurate identification due to their phenotypic similarities [2, 3, 4].

A. calcoaceticus (Genomic Species 1) is an environmental species with limited clinical significance. It is part of the ACB complex and is genetically related to other species within the complex. While it is often associated with environmental sources such as soil and water, its role in clinical infections is not as well-defined [3, 4].

A. baumannii (Genomic Species 2) is the most clinically important species within the ACB complex. It is a gram-negative bacterium responsible for various infections, particularly in healthcare settings. A. baumannii is associated with multidrug resistance, making it challenging to treat. It is a major cause of nosocomial outbreaks and has been extensively studied due to its impact on patient health [1, 2].

Acinetobacter pittii (Genomic Species 3) is another member of the ACB complex and is closely related to A. baumannii. It shares genetic similarities with other species in the complex, making accurate identification difficult using conventional methods. It has been isolated from clinical specimens and is associated with healthcare-associated infections [3, 4].

A. nosocomialis (Genomic Species 13TU) is part of the ACB complex and is closely related to other species within the complex. It shares genetic traits with A. baumannii and A. pittii, making it challenging to distinguish phenotypically. Like other species in the complex, A. nosocomialis has been isolated from clinical specimens and is associated with nosocomial infections [2, 3].

Although not originally included in the ACB complex, A. seifertii has been proposed for inclusion within the complex. It was previously called Acinetobacter genomic species “close to 13TU.” This species has been isolated from clinical specimens and contributes to the complexity of Acinetobacter species identification [3, 4].

Acinetobacter lactucae (Synonym of A. dijkshoorniae) formerly known as Acinetobacter NB14, is closely related to A. pittii and A. nosocomialis. It has been identified as a high-priority pathogen, especially in intensive care units. A. lactucae is associated with clinical infections, and its inclusion within the ACB complex adds to the challenges of accurate identification [3, 4].

A. baumannii is a short, almost round, rod-shaped (coccobacillus) Gram-negative bacterium. It lacks flagella for locomotion but exhibits twitching or swarming motility, possibly due to type IV pili or exopolysaccharide activity. While other species of the Acinetobacter genus are often found in soil [1, 2], A. baumannii is primarily isolated from hospital environments [1], making it an important nosocomial pathogen. It can be an opportunistic pathogen, particularly affecting individuals with compromised immune systems [1, 2, 3].

The taxonomy of the Acinetobacter genus has evolved, leading to the recognition of distinct species within the A. calcoaceticus-A. baumannii complex [3]. Initial taxonomic studies in the mid-1980s identified A. baumannii as a novel species, separate from other Acinetobacter species [3, 4]. Further refinements in taxonomy included the proposal of new species, such as A. pittii “Genomic Species 3” and A. nosocomialis“Genomic Species 13TU” [1, 4]. The bacterium’s ability to adapt and thrive in diverse environments underscores its clinical significance and challenges in infection control.

2.2 Clinical relevance and epidemiology

A. baumannii is a prominent pathogenic bacterium associated with various healthcare-associated infections, posing significant challenges to medical communities worldwide [1, 2]. Its clinical significance is underscored by its ability to cause a wide range of infections, its propensity for antibiotic resistance, and its capacity for persistence in hospital environments [5]. It commonly colonizes respiratory secretions, wounds, urine, and various medical equipment within hospital environments [5]. The risk of acquiring an A. baumannii infection is heightened in individuals with prior antibiotic exposure, intensive care unit (ICU) admissions, central venous catheter usage, and mechanical ventilation or hemodialysis [6]. Infections often target organ systems with high fluid content, such as the respiratory tract, cerebrospinal fluid, peritoneal fluid, and urinary tract [3]. Notably, outbreaks of Acinetobacter infections, particularly pneumonia, have been reported in healthcare settings [1, 7, 8].

The epidemiology of A. baumannii presents a significant public health concern, particularly within healthcare settings. This ubiquitous pathogen is capable of causing both community and healthcare-associated infections (HAIs), with the latter being the more common form [9]. A. baumannii has gained attention due to its extensive antimicrobial resistance and ability to initiate large, often multi-facility nosocomial outbreaks [5]. These outbreaks are facilitated by its tolerance to desiccation and its multidrug resistance, allowing it to persist in hospital environments [10].

The epidemiology of A. baumannii infections is complex, with the coexistence of both epidemic and endemic diseases. Epidemic infections can lead to outbreaks, while endemic infections are often fueled by the selective pressure of antimicrobials [11]. Notably, severe A. baumannii infections, such as bacteremia or pneumonia in intensive care unit patients undergoing intubation, are not associated with higher attributable mortality rates or increased hospital stays [12]. The pathogen mainly causes pulmonary, urinary tract, bloodstream, or surgical wound infections, with invasive procedures and broad-spectrum antimicrobial use being significant risk factors [4, 5]. Despite its clinical importance, knowledge about A. baumannii is less developed than other pathogens, and accurate identification remains challenging [5]. Nevertheless, the organism’s ability to accumulate antimicrobial resistance mechanisms, resistance to desiccation, and propensity to cause outbreaks make it a noteworthy and challenging pathogen in healthcare settings.

2.3 Virulence factors and pathogenicity

Virulence factors are crucial determinants that contribute to A. baumannii’s ability to establish infections, evade host defenses, and cause disease. Several virulence factors have been identified, shedding light on this bacterium’s pathogenesis and virulence mechanisms.

One notable virulence factor is the presence of efflux pumps, which contribute to antibiotic resistance and facilitate the extrusion of antibiotics, limiting their effectiveness [13]. Additionally, β-lactamases and aminoglycoside-modifying enzymes significantly confer antibiotic resistance, further enhancing the bacterium’s ability to survive and cause infections [14].

Biofilm formation is another important virulence factor that enables A. baumannii to adhere to surfaces, including medical devices and equipment, contributing to its persistence in healthcare environments [10, 15]. The Bap protein and the csu locus are associated with biofilm production and pathogenicity, allowing A. baumannii to colonize and establish infections on medical surfaces [10].

Furthermore, iron acquisition systems are critical virulence factors that facilitate the acquisition of iron, an essential nutrient for bacterial growth, from the host environment [16]. Iron is crucial for bacterial survival and proliferation, and A. baumannii has developed mechanisms to scavenge iron from the host to support its growth during infection [17].

The outer membrane protein OmpA, phospholipases, membrane polysaccharide components, penicillin-binding proteins, and outer membrane vesicles are additional virulence factors identified in A. baumannii and contribute to its pathogenesis [18]. These factors play roles in host immune responses, bacterial adherence, and evasion of host defenses.

The aforementioned virulence factors confer A. baumannii as a formidable opportunistic pathogen known for its ability to cause severe nosocomial infections, particularly in intensive care units (ICUs) [19, 20, 21]. Its emergence as a public health threat is underscored by its escalating antibiotic resistance and its ability to cause various clinical manifestations, including pneumonia, septicemia, and meningitis [3].

A critical facet of A. baumannii’s pathogenicity is its ability to trigger a robust immune response upon infection. Toll-like Receptor 4 (TLR4) serves as a key pathogen recognition receptor, inducing the production of inflammatory cytokines, such as IL-6 and TNF-α, upon A. baumannii infection [22]. Activating the inflammasome pathway leads to pyroptosis and the release of pro-inflammatory cytokines, contributing to the host’s defense mechanisms against the infection [23].

A recent study has identified that A. baumannii secretes a bioactive lipid that triggers inflammatory signaling and cell death [22], further highlighting its capacity to induce immune responses. Specific virulence factors, such as phospholipases and outer membrane proteins, also contribute to its ability to adhere to host cells and evade immune recognition [24].

The epidemiology of A. baumannii infections suggests that it can cause outbreaks in healthcare settings, particularly ICUs. Cross-contamination between patients and the environment plays a significant role in its transmission [3]. This fact emphasizes the importance of infection control measures to prevent its spread and reduce hospital-acquired infections [3].

The pathogenicity of A. baumannii is multifaceted, encompassing antibiotic resistance, immune activation, biofilm formation, and virulence factor secretion. Its ability to trigger immune responses while evading host defenses contributes to its clinical impact and challenges in treatment.

3. Host immune responses to A. baumannii

3.1 Innate immune responses

3.1.1 Recognition and activation of innate immune cells

The host’s innate immune responses are pivotal in the initial recognition and defense against A. baumannii infection. Innate immune responses are orchestrated by a complex interplay between pattern-recognition receptors (PRRs) and various immune effectors [25]. Understanding these interactions is critical for developing novel therapeutic strategies, including vaccines and immunotherapeutics, to combat A. baumannii infections.

Recognition of A. baumannii by PRRs, such as Toll-like receptors (TLRs), initiates a cascade of events leading to the production of inflammatory cytokines and chemokines [26]. These signaling molecules recruit innate immune effectors, including neutrophils and macrophages, to the site of infection. Neutrophils, in particular, play a crucial role in the control of A. baumannii infections [27]. They are rapidly recruited to the site of infection and contribute to bacterial clearance through phagocytosis and the release of antimicrobial peptides and reactive oxygen species.

However, A. baumannii has evolved mechanisms to evade immune responses and establish infections. Its ability to develop antibiotic resistance further complicates treatment strategies, highlighting the need for alternative approaches such as immunomodulation [28].

3.1.2 Inflammatory cytokine production

The host’s innate immune responses play a critical role in recognizing and responding to A. baumannii infection, producing inflammatory cytokines and chemokines that orchestrate the immune defense against the pathogen [26].

The host’s PRRs recognize pathogen-associated molecular patterns (PAMPs) on the bacterium’s surface. This recognition triggers a cascade of events that lead to the activation of downstream signaling pathways, ultimately producing pro-inflammatory cytokines and chemokines [27].

Inflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), are key mediators of the immune response against A. baumannii infection [28]. These cytokines play pivotal roles in promoting inflammation, recruiting immune cells to the site of infection, and enhancing immune cell activation. For instance, neutrophils, essential players in controlling A. baumannii infection, are rapidly recruited to the site of infection in response to cytokine signals [29]. Neutrophils contribute to bacterial clearance through phagocytosis and the release of antimicrobial peptides and reactive oxygen species [30].

However, A. baumannii has evolved mechanisms to evade immune responses, including modulating the expression of virulence factors to counteract host immune attacks [31]. This tug-of-war between the bacterium and the host’s immune system underscores the complexity of the immune response against A. baumannii infection.

3.1.3 Phagocytosis and intracellular killing

Phagocytosis, the process by which immune cells engulf and internalize pathogens, is pivotal in the initial defense against A. baumannii. Neutrophils, macrophages, and other professional phagocytes are essential effectors in host defense against this bacterium [26]. Neutrophils, in particular, are rapid responders recruited to the site of infection and are crucial for controlling A. baumannii infections [26]. Upon encountering A. baumannii, neutrophils undergo activation, leading to flattening and the extension of pseudopods, which initiate phagocytosis [32]. This process involves recognizing bacterial components through pattern-recognition receptors, such as TLRs, on the surface of neutrophils. These interactions trigger bactericidal mechanisms, including oxidative bursts and the production of cytokines and chemokines, amplifying the immune response against the pathogen [33]. Furthermore, neutrophils have been shown to release neutrophil extracellular traps (NETs), web-like structures composed of DNA, histones, and antimicrobial proteins, as part of their defense against A. baumannii [32].

In addition to phagocytosis, intracellular killing mechanisms are critical for neutralizing A. baumannii within immune cells. Once phagocytosed, immune cells destroy the engulfed bacteria through various means. Professional phagocytes can generate reactive oxygen species (ROS) through oxidative burst, which is toxic to internalized pathogens [33]. These ROS contribute to the bactericidal activity of immune cells, aiding in the elimination of A. baumannii [33]. Moreover, the production of antimicrobial peptides and enzymes within phagolysosomes further enhances the intracellular killing of A. baumannii [33].

While neutrophils and other immune cells play a crucial role in phagocytosis and intracellular killing, the ability of A. baumannii to survive within host cells and manipulate immune responses poses challenges in combating infections caused by this pathogen.

3.2 Adaptive immune responses

3.2.1 T cell-mediated responses

T cell-mediated responses, including CD4+ helper T cells and CD8+ cytotoxic T cells, are essential components of the adaptive immune system’s defense against A. baumannii. These T cells recognize specific antigens presented by antigen-presenting cells (APCs) and respond by proliferating and differentiating into armed effector T cells. CD4+ T cells help other immune cells, such as B cells and macrophages, enhance the immune response. CD8+ T cells target and eliminate A. baumannii-infected host cells [26].

Despite the importance of T cell-mediated responses, understanding the host immune interaction with A. baumannii still needs to be completed. Developing effective vaccines and immunotherapies to combat A. baumannii infections requires a deeper comprehension of the host immune mechanisms, identifying key virulence factors targeted by the immune system, and the modulation of T cell responses to enhance their efficacy against this pathogen. The ongoing efforts to elucidate the immune response to A. baumannii will contribute to developing innovative strategies to mitigate its impact on global health.

3.2.2 B cell-mediated responses

The role of B cell-mediated responses in combating A. baumannii infections is paramount. B cells, a crucial component of the adaptive immune system, contribute to the defense against pathogens by producing antibodies and participating in immune memory.

B cells play a central role in recognizing specific antigens presented by A. baumannii [33]. Upon encountering these antigens, B cells become activated and undergo clonal expansion, producing antibodies specifically tailored to bind to the pathogen. These antibodies can neutralize A. baumannii by preventing its interaction with host cells and opsonizing the bacterium for phagocytosis by innate immune cells [34].

The antibodies produced by B cells can initiate various effector mechanisms that contribute to the clearance of A. baumannii infections. These mechanisms include complement activation, which enhances opsonization and lysis of the pathogen, and antibody-dependent cellular cytotoxicity (ADCC), where immune cells such as neutrophils and macrophages recognize and eliminate antibody-bound A. baumannii [34].

One of the key functions of B cells is to establish immunological memory. Memory B cells are long-lived and can rapidly respond to re-infection with A. baumannii. Upon re-exposure to the pathogen, memory B cells can quickly differentiate into antibody-secreting plasma cells, leading to a faster and more robust immune response. This memory response is essential for preventing recurrent infections and providing long-term protection [34].

Despite the critical role of B cell-mediated responses, challenges remain in fully understanding their specific interactions with A. baumannii antigens and elucidating the antigenic targets that elicit protective B cell responses and characterizing the antibody repertoire generated during A. baumannii infection will contribute to the development of effective vaccines and immunotherapies. Additionally, the impact of A. baumannii’s ability to adapt and regulate virulence factor expression on B cell responses requires further investigation.

3.2.3 Antibody production and opsonization

Antibodies, also known as immunoglobulins (Ig), are produced by B lymphocytes in response to the presence of antigens, such as A. baumannii components. Upon exposure to A. baumannii, B cells recognize specific antigens, leading to their activation and subsequent differentiation into plasma cells. These plasma cells secrete antibodies tailored to target A. baumannii antigens, facilitating their neutralization and removal from the body [35, 36]. The production of antibodies, particularly IgG, is a key feature of the adaptive immune response against A. baumannii infections.

Opsonization is a crucial process by which antibodies bind to pathogens, marking them for recognition and engulfment by immune cells such as phagocytes. Antibodies attached to A. baumannii enhance the efficiency of phagocytosis by facilitating the interaction between the pathogen and immune cells. This opsonic effect improves the clearance of A. baumannii from the host’s bloodstream and infected tissues. Opsonization is particularly important in countering A. baumannii’s ability to evade the host immune response through mechanisms such as capsule formation and outer membrane protein variation [34, 35].

Immunization strategies involving A. baumannii antigens, such as outer membrane vesicles (OMVs) or capsular polysaccharides, have shown promise in inducing robust antibody responses [35]. Immunization with A. baumannii OMVs has been demonstrated to elicit high levels of IgG antibodies, which are associated with opsonization and improved antibiotic sensitivity of the pathogen [35]. These antibodies can enhance the susceptibility of A. baumannii to antibiotics, potentially enhancing the effectiveness of antibiotic treatments [35].

4. Mechanisms of immune evasion by A. baumannii

4.1 Capsule and outer membrane proteins

The capsule of A. baumannii is a protective polysaccharide layer that envelops the bacterium, enabling it to evade recognition by host immune cells. This structure hampers opsonization, a process in which antibodies or complement proteins coat the pathogen, marking it for phagocytosis by immune cells. By masking surface antigens and inhibiting complement deposition, the capsule shields A. baumannii from immune detection and subsequent destruction [37].

A. baumannii employs outer membrane proteins (OMPs) as versatile tools to modulate interactions with the host immune system. These OMPs are pivotal in mediating adhesion, invasion, and immune evasion. Through antigenic variation and phase variation, A. baumannii can alter the expression of specific OMPs, evading immune surveillance and memory. Additionally, some OMPs have been shown to interact with host receptors, thereby dampening immune responses and promoting bacterial survival [31].

4.2 Efflux pumps and antibiotic resistance

Efflux pumps are integral membrane proteins that transport many molecules, including antibiotics, out of bacterial cells. A. baumannii employs efflux pumps to expel antibiotics from within the bacterial cell, thereby reducing intracellular drug concentrations and rendering antibiotics less effective. Efflux pumps contribute to multidrug resistance (MDR) in A. baumannii, enabling the bacterium to survive exposure to various antibiotics, including aminoglycosides, fluoroquinolones, and beta-lactams [13, 27].

Several classes of efflux pumps are associated with A. baumannii’s antibiotic resistance. Notably, the major facilitator superfamily (MFS), resistance-nodulation cell division (RND) family, small multidrug resistance (SMR) family, and multidrug and toxic compound extrusion (MATE) family of efflux pumps are implicated in the bacterium’s ability to expel antibiotics and evade host immune responses [13, 27]. These pumps have three main components: the outer membrane channel, the periplasmic lipoprotein, and the inner membrane transporter.

Efflux pumps reduce antibiotic susceptibility by preventing antibiotics from accumulating within A. baumannii cells. This phenomenon leads to elevated minimum inhibitory concentrations (MICs) of antibiotics required to inhibit bacterial growth. Consequently, the bacterium becomes more resistant to antibiotic treatments, limiting the effectiveness of conventional therapeutic approaches [13, 27].

4.3 Biofilm formation

Biofilms are complex communities of bacterial cells encased within a self-produced extracellular matrix. This matrix, primarily composed of polysaccharides, proteins, and DNA, protects bacteria from external threats, including host immune cells and antibiotics. A. baumannii’s ability to form biofilms allows it to attach to biotic and abiotic surfaces, making medical devices and equipment potential reservoirs for infection [10, 15, 38].

Biofilm formation enables A. baumannii to evade the host immune response through multiple mechanisms. The biofilm matrix acts as a physical barrier that hinders the penetration of immune cells and antibodies, thereby reducing the efficacy of the immune system’s defense mechanisms. Additionally, the altered physiology of bacterial cells within the biofilm contributes to decreased susceptibility to immune clearance. Immune cells, such as neutrophils and macrophages, struggle to effectively target and eliminate bacteria embedded within the biofilm structure [10, 15, 38].

A. baumannii biofilms are frequently associated with chronic infections, particularly those involving medical devices like catheters and ventilators. These infections are challenging to treat due to the inherent resistance of biofilm-embedded bacteria to antibiotics. The biofilm matrix provides a protective environment that shields bacteria from the effects of antibiotics and prevents their effective eradication. As a result, chronic infections caused by A. baumannii biofilms can persist despite antibiotic treatment, leading to prolonged patient suffering and increased healthcare costs [15, 38].

4.4 Modification of surface structures and antigenic variation

A. baumannii employs various strategies to modify its surface structures, effectively masking its presence from the host immune system. One of the key modifications is the alteration of lipopolysaccharides (LPS) and OMPs, which are major targets for host immune recognition. By modifying these surface molecules, A. baumannii can evade detection by immune cells and antibodies, reducing the effectiveness of the immune response. Additionally, A. baumannii may shed OMVs containing modified surface components, further contributing to immune evasion [31, 39].

Antigenic variation is a sophisticated strategy employed by A. baumannii to continually alter its surface antigens, making it difficult for the host immune system to recognize and mount an effective response. A. baumannii possesses a diverse repertoire of surface antigens, such as pili and fimbriae, which can undergo rapid changes through genetic recombination and mutation. This dynamic antigenic variation hinders the host’s ability to generate a robust and lasting immune response, allowing A. baumannii to evade immune surveillance and persist within the host [31, 37, 39].

Modifying surface structures and antigenic variation collectively contribute to A. baumannii’s ability to escape immune recognition and clearance. These mechanisms limit the host’s ability to develop a strong and sustained immune response against the bacterium. As a result, A. baumannii can persist within the host, leading to chronic infections that are challenging to treat with conventional antibiotics. This persistence is particularly problematic in healthcare settings, where A. baumannii can cause ventilator-associated pneumonia and other hospital-acquired infections [31, 37, 39].

4.5 Suppression of immune signaling pathways

A. baumannii utilizes several mechanisms to dampen host immune signaling pathways, impairing the immune response and promoting its survival within the host environment. One key strategy involves interference with PRRs, crucial in initiating immune responses upon pathogen detection. By inhibiting PRR signaling, A. baumannii can thwart the activation of immune cascades, reducing the recruitment of immune effectors and impeding the production of inflammatory cytokines and chemokines necessary for an effective immune response [24, 26].

Neutrophils are essential components of the innate immune system and play a critical role in combatting bacterial infections. A. baumannii employs strategies to counteract neutrophil responses, impairing their recruitment and effector functions. Studies have shown that A. baumannii can interfere with neutrophil recruitment to the site of infection, leading to delayed reactions and reduced bactericidal activity. Furthermore, the bacterium can modulate cytokine and chemokine production, hindering the optimal activation of neutrophils and other immune cells required for effective bacterial clearance [24, 26, 33].

A. baumannii employs a multifaceted approach to evade host immune responses, including suppressing key signaling pathways involved in immune activation. This evasion strategy impairs the initial recognition of the pathogen by the host and dampens the subsequent immune cascade required for efficient bacterial clearance. By targeting these immune signaling pathways, A. baumannii can establish chronic infections and evade host defenses, contributing to its persistence and clinical significance as a nosocomial pathogen [24, 26].

5. Impact of host: pathogen interactions on disease outcome

5.1 Factors influencing disease severity and prognosis

The severity of A. baumannii infections has a direct impact on patient prognosis. Studies have shown that higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores indicate that patients with more severe disorders are at increased risk of mortality. Patients with underlying severe comorbidities, such as hematologic malignancies, are particularly vulnerable to poor outcomes in the presence of A. baumannii infections [40, 41, 42].

Appropriate antimicrobial therapy is a critical determinant of patient outcomes in A. baumannii infections. Studies have demonstrated that timely and effective antimicrobial treatment reduces mortality rates, particularly in severely ill patients. However, the impact of antimicrobial therapy may vary based on the severity of infection, underlying conditions, and other risk factors [40, 41].

Several factors contribute to the severity and prognosis of A. baumannii infections. These include the presence of neutropenia, which weakens the immune response, and the use of invasive procedures, which can introduce and spread diseases. Additionally, the prior use of specific antibiotics, such as carbapenems, has been identified as a risk factor for poor outcomes. Mechanical ventilation and initial immunosuppression are also associated with increased mortality rates in A. baumannii bloodstream infections [41].

MDR is a significant concern in A. baumannii infections, potentially limiting treatment options and contributing to poorer outcomes. While MDR may not always be a direct risk factor for mortality, it can impact the choice of appropriate antimicrobial therapy, potentially leading to treatment failure and increased mortality rates [42].

5.2 Host genetic susceptibility

Host genetic susceptibility refers to inherited gene variations that can affect an individual’s susceptibility to infections and their ability to mount an effective immune response. The genetic diversity among individuals can impact the interaction between A. baumannii and the host’s immune system. Some genetic variations may enhance the host’s ability to recognize and combat the pathogen, while others may compromise the immune response and increase susceptibility to infection.

Host genetic factors play a role in shaping both innate and adaptive immune responses to A. baumannii infections. Variations in genes encoding immune receptors, cytokines, and other immune-related molecules can affect the intensity and effectiveness of the immune response. For example, genetic variations in TLRs or cytokines may influence the recognition of A. baumannii and subsequent activation of immune signaling pathways. These genetic differences can impact the production of pro-inflammatory cytokines, chemokines, and other immune mediators, which affect the recruitment and activation of immune cells [39, 43].

A. baumannii employs various virulence factors to establish infection and evade host immune responses. The host’s genetic background can influence these virulence factors’ effectiveness. For instance, host cell surface receptors or signaling molecule variations may affect the pathogen’s ability to adhere to and invade host cells. Additionally, genetic variations in the host may impact the immune system’s recognition of specific virulence factors, influencing the overall immune response to the infection [39, 43].

6. Potential therapeutic targets for A. baumannii infections

6.1 Antibiotic resistance mechanisms and novel antimicrobial strategies

The increasing prevalence of MDR, extensive drug-resistant (XDR), and even pan-drug-resistant (PDR) strains of A. baumannii has raised concerns about limited treatment options and the need for novel antimicrobial strategies [44, 45].

The development of antibiotic resistance in A. baumannii is a complex process driven by various genetic and physiological factors. The resistance mechanisms primarily involve regulating antibiotic transportation through bacterial membranes, alteration of the antibiotic target site, and enzymatic modifications that neutralize antibiotics.

The rise of MDR, XDR, and PDR A. baumannii strains can be attributed to extensive antibiotic abuse and poor stewardship in healthcare settings. Long hospitalization stays, catheters, mechanical ventilation, and compromised immune systems further contribute to the emergence of resistant strains [44]. In recent years, there has been a growing awareness of the need for appropriate antibiotic use, infection prevention, and surveillance strategies to curb the spread of antibiotic resistance.

Advances in next-generation sequencing techniques have revolutionized the diagnosis of severe A. baumannii infections. These techniques allow for the rapid identification of specific resistance genes, enabling timely diagnosis and the design of personalized therapeutic regimens based on the pathogen’s resistance profile [44]. Tailoring treatment to the identified resistance mechanisms enhances the likelihood of successful outcomes and reduces the risk of treatment failure.

Researchers are exploring novel antimicrobial strategies to combat A. baumannii infections, especially those caused by MDR and XDR strains. One such approach involves the development of alternative antibiotics or antimicrobial agents that target different bacterial pathways, reducing the likelihood of cross-resistance [45]. Efforts are also underway to investigate combination therapies that synergistically enhance the efficacy of existing antibiotics, potentially overcoming resistance mechanisms.

6.2 Targeting virulence factors and host: pathogen interactions

A. baumannii deploys a variety of virulence factors to establish infections and evade host defenses. Targeting these virulence mechanisms presents a potential strategy to disrupt the pathogenicity of A. baumannii.

Understanding the interactions between A. baumannii and the host immune system is essential for developing effective therapeutic interventions. A. baumannii has evolved mechanisms to evade host immune responses and establish persistent infections. By disrupting these interactions, researchers aim to enhance the host’s ability to clear the infection and improve treatment outcomes [45, 46].

Researchers are investigating various approaches to target virulence factors and host–pathogen interactions in A. baumannii infections. These strategies include the development of new antimicrobial agents that inhibit essential bacterial functions and therapies that specifically disrupt virulence mechanisms without killing the bacterium. For example, inhibiting OmpA, a key virulence factor, could weaken the bacterium’s ability to form biofilms and evade immune responses, making it more susceptible to clearance by the host [46].

6.3 Immunotherapeutic approaches

The emergence of MDR and XDR A. baumannii strains has led to limited treatment options, with traditional antibiotics becoming increasingly ineffective. This resistance is attributed to the mechanisms mentioned earlier. Consequently, alternative strategies, including immunotherapeutic approaches, are being explored to address the growing threat of A. baumannii infections.

Immunization trials are being considered as a promising avenue for combatting A. baumannii infections. Researchers are focusing on developing vaccines that target specific antigens or epitopes associated with the pathogen. Several antigens and peptides have been proposed for active and passive immunizations [47].

Monoclonal antibody (MAb) therapy has emerged as a promising immunotherapeutic strategy against A. baumannii infections. MAbs are designed to recognize and neutralize bacterial targets specifically. Researchers have developed MAbs that target different components of A. baumannii, such as the bacterial capsule, to enhance opsonophagocytosis and clearance by immune cells [48]. These MAbs have demonstrated efficacy in murine models, significantly improving survival rates and reducing bacterial loads [48]. Furthermore, combining monoclonal antibody therapy with traditional antibiotics, such as colistin, has shown synergistic effects and improved protection [48].

While immunotherapeutic approaches, including monoclonal antibody therapy and vaccine development, hold promise for addressing A. baumannii infections, challenges remain. Designing vaccines that provide broad protection against various strains and do not affect the host microbiota or proteome is complex [47]. Additionally, the clinical translation of immunotherapeutic strategies requires rigorous preclinical testing and validation.

7. Conclusion

This book chapter has provided a comprehensive overview of host–pathogen interactions in A. baumannii infections, uncovering immune evasion mechanisms and potential therapeutic targets. While challenges persist, the remarkable progress in understanding these interactions offers hope for innovative treatments and strategies to combat A. baumannii infections and improve patient outcomes.

As we conclude this exploration, several implications for future research and therapeutic interventions emerge. Firstly, the need for a deeper understanding of the host immune response and the molecular mechanisms of A. baumannii’s immune evasion strategies remains paramount. Identifying specific virulence factors and the regulatory networks that govern their expression could provide new targets for intervention.

Advancing research should also focus on unraveling the dynamics of multidrug resistance in A. baumannii and developing innovative strategies to circumvent resistance mechanisms. The application of cutting-edge technologies, such as genomics and proteomics, holds promise in identifying novel therapeutic targets and potential biomarkers for early detection and prognosis.

The potential of immunomodulatory agents and host-directed therapies in therapeutic interventions should be rigorously explored. Designing targeted strategies that enhance the host’s immune response while inhibiting A. baumannii’s immune evasion mechanisms could revolutionize treatment outcomes.

Collaboration between interdisciplinary teams, including microbiologists, immunologists, pharmacologists, and clinicians, will be instrumental in translating research findings into effective therapeutic interventions. Integrating computational modeling and artificial intelligence could expedite drug discovery and enhance our understanding of complex host–pathogen interactions.

Conflict of interest

The authors declare no conflict of interest.