Recent advancement of the host immunity against Listeria monocytogenes

Introduction

Listeria monocytogenes (Lm) is a Gram-positive facultative anaerobic bacterium, which is also a facultative intracellular pathogen. It is widely distributed in the natural environment and can replicate at low temperatures and a wide range of pH values.¹ Currently, there are 10 recognized strains of Listeria internationally, among which Lm is the only species that can cause human diseases, leading to human Listeriosis with a high mortality rate.² Among those recognized Listeria serovars, serotype 4b strains (Lineage I) exhibit heightened epidemic potential due to virulence factors, contrasting historical assumptions of uniform pathogenicity across serovars.^2,3

Lm is a typical foodborne pathogenic bacterium that is mainly transmitted through contaminated food.⁴ It is also present in most foods such as unpasteurized cheeses or meat products, pre-packaged sandwiches, cold-smoked fish, salads, fruits, etc.⁵ Other food sources such as caramel apples or mung bean sprouts are also associated with Listeriosis (Figure 1). ⁶

Listeriosis is usually divided into invasive and non-invasive forms. Non-invasive Listeriosis mainly occurs in people with low immunity. Infected individuals may experience fever, muscle aches, and gastrointestinal symptoms. Invasive Listeriosis mainly occurs in certain elderly individuals, pregnant women, newborns, and those with weak immunity, increasing the likelihood of serious symptoms such as meningitis, endocarditis, sepsis, septicemia, miscarriage or stillbirth (Figure 1). ^7,8

Currently, antibiotics such as ampicillin, penicillin, and amoxicillin are commonly used in clinical practice to treat Lm disease. The most commonly used treatment for invasive Listeria infection is combination therapy with ampicillin and gentamicin, and the effectiveness of gentamicin combination therapy has also been preliminarily confirmed in recent clinical studies.^9,10 Although Lm is susceptible to most antibiotics, it also exhibits intrinsic resistance to certain antimicrobial drugs. Additionally, Lm can increase its tolerance to antibiotics through stress responses such as reducing cell membrane permeability, increasing efflux pump activity, altering antibiotic structure, or changing cell components that serve as antibiotic targets¹¹—diverging from earlier “uniform susceptibility” models. This complexity, stemming from Lm’s facultative intracellular lifestyle and barrier-transgressing capabilities (eg, blood-brain/placental penetration), complicates antibiotic efficacy and necessitates immune-focused strategies.

It is now clear that the cephalosporin antibiotics have been shown to have no activity against Lm. Nevertheless, cephalosporins are still frequently used as empirical treatment for infections that have not been definitively diagnosed.⁶ With the increasing resistance of Lm to antibiotics and the rare and sporadic cases of Listeriosis, it is challenging to conduct clinical trials, leading to increased difficulty in treating Listeriosis.⁹ Finding effective methods to combat Lm remains a significant challenge. Thus, this review synthesizes advances in host-barrier defenses, innate/adaptive immunity, and emerging immunomodulatory approaches against Lm, aiming to bridge mechanistic insights and clinical innovation for high-risk populations.

Immune Response to Lm

When Lm invades the body, the innate immune response serves as the first line of defense against foreign pathogens, mainly by combating Lm infection through three aspects: immune barriers, innate immune cells, and innate immune molecules.

Barrier System

Intestinal Barrier

According to research, gut microbiota acts as the first line of defense against pathogenic Lm infection, playing a role in maintaining host nutrition, immunity, metabolism, and resistance to pathogens.¹² During Lm infection, there are complex interactions between gut microbiota and the normal bacterial community.

The gut microbiota can bind to receptors on the intestinal epithelial cells to block the interaction between pathogens and epithelial cells, or inhibit intestinal pathogens directly or indirectly by producing antimicrobial peptides or competing for nutrients.¹³ Lactobacillus and Bifidobacterium secrete antimicrobial peptides to inhibit the growth of Lm,¹⁴ while Clostridium achieves anti-infection purposes by reducing the ability of Lm to colonize the gastrointestinal tract. Recently, Tong Jin et al found that Akkermansia muciniphila can play an anti-infection role by enhancing the intestinal barrier function and increasing the level of arachidonic acid.

Short-chain fatty acids (SCFAs) are metabolic products produced by the gut microbiota, mainly including acetic acid, propionic acid, and butyric acid. Due to the ability of SCFAs to protect intestinal barrier integrity by promoting the formation of tight junctions (TJ),¹⁵ they play an important role in resisting colonization and dissemination of Lm, as well as regulating inflammation. SCFAs can directly inhibit bacterial growth by disrupting cell metabolism and regulating intracellular pH.¹⁶ They also regulate the reactions of multiple Toll-like receptors (TLRs) and Tumor necrosis factor-α (TNF-α) by inhibiting histone deacetylase (HDAC) to promote proliferation of intestinal epithelial cells and enhance the expression of antimicrobial peptides in the gut microbiota to weaken pathogen colonization.¹⁷ Additionally, SCFAs can inhibit protein kinase B (PKB) and nuclear factor kappa-B (NF-κB) by binding to G protein-coupled receptors (GPCR) on the cell surface, reducing inflammation and improving intestinal epithelial barrier function.¹⁸ The breakdown metabolites of tryptophan and butyric acid can stimulate group 3 innate lymphoid cells (ILC3) in intestinal epithelial cells to produce interleukin 22 (IL-22),¹⁹ which is capable of maintaining intestinal homeostasis and facilitating recovery during intestinal infections.²⁰ In addition, intestinal epithelial cells (IECs) can secrete a bactericidal protein – small proline-rich protein 2A (SPRR2A) rich in proline, which selectively kills Lm by disrupting cell membranes.²¹

From the above, it can be seen that the intestinal flora and its metabolites are essential in combating Lm infection and inflammation response, however, their mechanism of action is complex and requires further research.

Blood-Brain Barrier

Bacterial meningitis has a high incidence and mortality rate, among which Lm is one of the main causes of adult bacterial meningitis.²² Studies have shown that Lm can pass through the intestinal barrier via the surface virulence factor internalin,²³ enter the bloodstream, and then transfer to the brain tissue. The central nervous system (CNS) has a specific protective barrier – the blood-brain barrier (BBB), which is composed of endothelial cells of capillary walls, astrocyte end-feet, and pericytes,²⁴ preventing harmful substances like toxins and pathogens from entering the brain to maintain brain homeostasis.²⁵

Studies have shown that Lm secretes listeriolysin-O (LLO) which can activate the NF-κB pathway in endothelial cells, promote the transcription of inflammatory factors such as IL-1β and TNF-α, thereby disrupting the integrity of BBB. At the same time, LLO can also induce the production of cell surface adhesion molecules P-selectin, E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), while the expression of inflammatory factors such as IL-1β and TNF-α can enhance LLO-induced ICAM-1 expression, further mediating cell adhesion and promoting the entry of white blood cells into the CNS.²⁶ The surface protein InlB of Lm also upregulates the expression of caspase-8 inhibitory protein FLIP (FADD-like IL-1β-converting enzyme) through the InlB/c-Met/PI3Kα-dependent cell pathway, thereby mediating the inactivation of the Fas cell death pathway in infected monocytes, extending the lifespan of infected cells, and providing opportunities for central invasion by crossing BBB.²⁷

Lm infection can cause a series of inflammatory reactions, leading to infiltration of inflammatory cells and increased release of inflammatory factors, thus disrupting the integrity of BBB and ultimately leading to bacterial meningitis. Therefore, we can protect the integrity of BBB and enhance the body’s ability to resist Lm infection by regulating inflammatory factors.

Placental Barrier

Pregnant women, as is well known, experience an increase in progesterone levels, which suppresses individuals’ immune function, making pregnant women highly susceptible to Lm infection. The placental barrier (PB) is composed of cells at the maternal-fetal interface, primarily including chorionic trophoblast cells, syncytiotrophoblast cells, extrachorionic trophoblast cells, and metamyelocytes, which can separate maternal blood from fetal blood.²⁸

According to reports, when Lm infects decidual macrophages, it induces macrophages to express Perforin-2, thereby inhibiting Lm colonization on the placenta and killing Lm.²⁹ Infected placental cells can also produce IL-1β, activating monocytes’ inflammasome to prevent Lm infection.³⁰ It is worth mentioning that decidual natural killer cells (dNK cells) can selectively transfer their highly expressed antimicrobial peptide granulysin (GNLY) to extracellular trophoblast cells through nanotubes, targeting and killing Lm.³¹

In addition, a small number of Lm can also invade the human body through damaged skin and corneal epithelium. Therefore, the skin mucosal barrier and corneal epithelium also play a certain role in resisting Lm infection.

Innate Immune Cells

Macrophages

Macrophages are an important component of the innate immune system, with functions such as phagocytosis and antigen presentation. Upon stimulation by Lm, macrophages undergo polarization into M1 (Classically activated macrophages, M1) and M2 (Alternatively activated macrophages, M2) subtypes. M1 cells secrete pro-inflammatory cytokines, such as IL-1 and IL-6 mediating inflammatory responses,³² while M2 cells secrete anti-inflammatory cytokines like IL-10 mediating tissue repair.³³ In response to Lm infection, macrophages first polarize towards the M1 type, triggering an inflammatory response to kill Lm.

After ingestion of Lm by macrophages, Myeloid differentiation factor 88 (MyD88)-dependent response genes are activated through TLRs, thereby activating the NF-κB signaling pathway, exerting an anti-infection effect.³⁴ The NF-κB signaling pathway is the main signaling pathway through which the body produces pro-inflammatory factors to combat Lm. Recent studies have found that GTP-binding protein 2 (DRG2) in macrophages can regulate the expression of IL-6 during the early stage of Lm infection. Lack of DRG2 reduces the transcriptional activity of NF-κB, increases host susceptibility to Lm, indicating the crucial role of DRG2 in combating Lm infection during early inflammatory response.³⁵ Research has also shown that macrophages regulate the production of inducible nitric oxide synthase (iNOS) through the NF-κB and JAK-STAT1 signaling pathways, inhibiting Lm proliferation. Meanwhile, studies have shown that inhibiting lipid droplet formation can reduce the intracellular survival rate of Lm.³⁶

After Lm infection, pro-inflammatory factors activate calcium homeostasis modulator family member 6 (CALHM6) in macrophages, and CALHM6 relocates from intracellular compartments to macrophage-NK cell synapses, promoting ATP release and controlling NK cell activation.³⁷ Joel et al found that type I Interferon (IFN) can inhibit macrophages’ bactericidal activity against Lm, and mice lacking the type I interferon receptor are resistant to Lm infection. The specific mechanism involves IFN-induced transmembrane protein 3 (IFITM3) which can inhibit the proteolytic activity in macrophages, thus facilitating the spread of Lm between cells.³⁸

Current studies have shown that macrophages in the innate immune system mainly rely on the M1 subtype NF-κB signaling pathway to induce the production of inflammatory factors, playing a role in anti-infection and anti-proliferation and spread of Lm. Subsequently, the M2 subtype of macrophages limits tissue damage and repairs injuries.³⁹ The specific mechanism of macrophages in response to Lm and targeted therapies still require further research.

Dendritic Cells

Dendritic cells (DCs), as professional antigen presenting cells (APCs), play important roles in activating and initiating T cell immune responses in both innate and adaptive immunity. Lm, as an intracellular bacterium, primarily induces cell-mediated immunity mediated by CD8⁺ T lymphocytes. Post-synaptic dendritic cells (psDCs) helps CD8⁺ T cell responses with the assistance of CD4⁺ T cells. Diego et al report that immune synapse formation facilitates lipid peroxidation and MHC-I upregulation in licensed dendritic cells for efficient priming of CD8⁺ T cells.⁴⁰ The immunological synapse can induce MHC I and lipid peroxidation both in vivo and in vitro. Lack of lysine-specific demethylase 5C in DCs increases inflammatory cell expression and decreases antigen presentation ability of conventional type 1 dendritic cells (cDC1s). CD8⁺ T cell responses are reduced in Lysine Demethylase 5C (KDM5C)-deficient mice. Therefore, KDM5C is a key regulatory factor in DCs.⁴¹ Wang et al recently report that mice lacking Zeb1 in cDC1s exhibit stronger resistance to Lm, suggesting Zeb1 as a potential target to enhance antibacterial functions of cDC1s.⁴²

Neutrophils

Neutrophils play various roles in combating infection after being infected by Lm, including degranulation and releasing reactive oxygen species (ROS) as well as chemotaxis, activation, and phagocytosis. The response of neutrophils to Lm mostly requires the activation of Ca²⁺ channels. Current studies have shown that Stromal-interaction molecule 1 (STIM1) calcium sensor is an effective target for activating neutrophils against Lm. Recently, Ning Wu discovered that Transmembrane Protein 16F (TMEM16F) repaired Lm toxin Listeriolysin O (LLO) which induced plasma membrane damage in T cells in vitro.⁴³ Most research on neutrophil antibacterial activity is related to extracellular bacteria, while the mechanism of action of neutrophils against Lm is still under further exploration.

Innate Immune Molecules

TLRs

TLRs are the most important innate immune molecules against Lm. TLRs are a type I transmembrane protein, mainly composed of extracellular domain, transmembrane domain, and cytoplasmic domain. The extracellular domain of TLRs is rich in leucine-rich repeat sequences (LRRs), which are mainly responsible for ligand recognition and binding. The cytoplasmic domain of TLRs and the cytoplasmic domain of members of the IL-1 receptor (IL-1R) family are highly homologous, thus referred to as the Toll-IL-1 receptor domain (TIR) (Figure 2A).⁴⁴

Figure 2 Schematic diagram of the host immune mechanism against Lm infection. (A) Inherent host immune response: APC recognizes Lm surface antigens via TLR2/TLR6 heterodimer or TLR5 homodimer, which interacts with MyD88. MyD88 attracts interleukin-1 receptor associated kinase (IRAK), which is phosphorylated and interacts with tumor necrosis factor receptor-associated factor 6 (TRAF-6), leading to activation of NF-κB; secondly, Lm is internalized by APC and enters cytoplasmic replication and secretes cyclicdeadenylate (c-di-AMP). c-di-AMP transmits infection signals to the stimulator of interferon genes (STING), triggering type I interferon (IFN) production. (B) Adaptive host immune response: APCs phagocytose Lm, process its antigens, and present them to CD8+ T cells, priming an adaptive response. Cytokines further stimulate CD8+ T cells, enabling them to execute cell-mediated immunity against Lm. Created in BioRender. Qu, S. (2025) https://BioRender.com/48n3dbj.

In the human body, there are ten confirmed members of the TLR family, namely TLR1-TLR10. Among the innate immune mechanisms against Lm, TLR2 is particularly important. TLR2 is expressed on various cell types such as intestinal epithelial cells, CD8⁺ T cells, but is most abundant in bone marrow-derived macrophages (BMMs). TLR2 mainly exerts its effects by forming heterodimers with other TLRs (such as TLR1, TLR6), which then bind to their respective ligands.⁴⁵ Several studies have shown that wild-type mice have significantly increased levels of IL-10 in the serum 3–4 days after Lm infection. However, mice lacking IL-10 have a stronger ability to clear bacteria after Lm infection compared to wild-type mice.⁴⁶ A comparison of the two can illustrate that IL-10 partially inhibits the innate immune response to Lm in mice. Recent studies have indicated that TLR2, along with the endosomal TLR-mediated signaling pathway, can increase the expression of IL-10, thereby inhibiting the innate immune response.⁴⁷ Recent research have showed that Lm activates multiple signaling pathways in mast cells, mainly modulating cytokine production. TLR2 mediates IL-6 and IL-13 synthesis and p38 activation. In contrast, TNF-α, IL-1β, and MCP-1 production, ROS release, mast cell degranulation, endocytic/bactericidal functions, and ERK/NF-κB activation are TLR2-independent, indicating the crucial role of TLR2 in regulating the synthesis of IL-6 and IL-13 during Lm infection in mast cells.⁴⁸

TLRs, as the most important innate immune molecules, play a role in resisting Lm invasion by activating downstream signaling pathways. Therefore, enhancing the ability of Toll-like receptors to resist Lm invasion can be used as a therapeutic approach.

C-Type Lectin Receptors

The structure domain of classical C-type lectin receptors (CLRs), C-type lectin-like domain CTLDs, consists of conserved amino acid sequences and Ca²⁺, where Ca²⁺ mainly assists CTLDs in recognizing carbohydrates. Recent studies by Chen et al have shown that C-type lectin domain containing 5A (CLEC5A) plays a crucial role in the innate immune response to Lm. Mice deficient in Clec5a^−/− show reduced production of IL-1β. Furthermore, Lm interacts with both TLR2 and CLEC5A on the cell surface, jointly activating TLR2 and CLEC5A to enhance pro-inflammatory responses.⁴⁹

On the surface of natural killer cells (NK cells), there exists a non-classical C-type lectin receptor, which recognizes ligands (mainly non-carbohydrates) that are independent of Ca²⁺. Hamid mentioned in the article that the killer cell lectin-like receptors (KIRs) located on the surface of NK cells can activate NK cells to release IFN-γ for indirect killing or directly kill Lm by binding with the corresponding ligands.⁵⁰

The C-type lectin receptor plays an important role in the host immune response against Lm, but its specific mechanism of action still needs further research.

Nucleotide-Binding Oligomerization Domain-Like Receptors

Nucleotide-binding oligomerization domain-like receptors (NLRs) are a type of pattern recognition receptor (PRR) located in the cytoplasm. They act as receptor proteins involved in the formation of inflammasome. The inflammasome is a multiprotein complex assembled in the cytoplasm, mainly composed of PRR, apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. It serves as a platform for the activation of caspase-1, secretion of pro-inflammatory cytokines IL-1β, IL-18, and caspase-1-dependent pyroptosis.⁵¹ Previous studies have shown that NOD-like receptor family, pyrin domain-containing protein 4 (NLRC4), NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3), and absent in melanoma 2 (AIM2) inflammasomes in macrophages contribute to caspase-1 activation, exacerbating inflammation and inducing cell pyroptosis.⁵² Hideki Hara et al report that lipoteichoic acid (LTA) produced after Lm infection can bind and activate NOD-like receptor family, pyrin domain-containing protein 6 (NLRP6), recruit and activate caspase-11 through ASC, thus promoting caspase-1 activation, IL-8 secretion, and worsening Lm infection.⁵³

Adaptive Immune Response to Lm

Cellular Immunity

CD8⁺ T Cells

Lm is a facultative intracellular bacterium, therefore, identifying the cells it infects is crucial for controlling infection. Lm antigens can be presented in multiple ways, depending on the type of infected cells.⁵⁴ Mayer et al identified 206 peptides among 79 Lm antigens, with 116 peptides presented on major histocompatibility complex I (MHC I) molecules,⁵⁵ elucidating that the antigen presentation of Lm is mainly through the MHC class I cytosolic antigen presentation pathway (Figure 2B). However, some studies have also shown the existence of MHC class II antigen presentation pathway for Lm, with the antigen processing and presentation depending on the type of infected cells and the compartmentalization of antigens.^45,56–58

After entering the cell membrane, Lm can induce the production of IFN-γ, induce the maturation of DCs in a MyD88-independent manner, thereby stimulating and activating T cells. CD8⁺ T cells are the most effective specific anti-Lm immune effector, playing an important role in clearing Lm infection and inducing the host to acquire lifelong protective immunity.^56,59 The primary immune response against Lm infection is mediated by two CD8⁺ T cell subsets: one is MHC Ia class-restricted CD8⁺ T cells, and the other is MHC Ib class H2-M3-restricted CD8⁺ T cells (Figure 3). Recent studies have found that there are subgroups of cells within the memory T cell population that exhibit effector-like characteristics, which highly express Killer Cell Lectin-like Receptor G1 (KLRG1) and lowly express CD27, belonging to a subgroup of CD27^loCD43^lo memory cells. Marie Louise Jahn et al confirm through adoptive transfer studies that these memory CD8 T cells expressing KLRG1 are core in protecting individuals from systemic Lm infection.⁴⁵ Therefore, the application of KLRG1⁺ memory T cells provides a new approach for clinical anti-Lm.

Figure 3 Main mechanisms of host immune defense against Lm.Neutrophils secrete defensins and phagocytose Lm. Macrophages activated via TLRs produce IFN-γ/IL-12, enhancing NK/Th1 responses. NK cells kill infected cells and secrete IFN-γ. γδT cells respond to pyrophosphates via cytolysis/IFN-γ. CTLs (MHCI) and Th1 cells (MHCII+IL-12) clear infection via TNF/IFN-γ, inducing macrophage ROI/RNI production and granulomas. B cells produce neutralizing antibodies against released antigens. (Created with Adobe Illustrator).

CD4⁺ T Cells

CD4⁺ T cells not only play an assisting role in helping CD8⁺ T cells establish a lifelong protective memory response to Lm, but also assist in the clearance of Lm by inducing dendritic cells to produce a large amount of T helper 1 (Th1) type cytokines.^46,60 The product of the Lm arpJ gene can upregulate the expression of tumor necrosis factor superfamily/tumor necrosis factor receptor superfamily (Tnfsf/Tnfrsf) molecules on APC cells, thereby inhibiting the differentiation of T helper 2 type (Th2) cell subset during Lm infection.⁶¹

The CD4⁺ T cell subpopulations of T helper 1 Cells (Th1), T helper 17 Cells (Th17), and regulatory cells (Tregs), all play certain roles in the host’s response to Lm infection (Figure 3). D’Orazio et al found that Th17 cells can produce the pro-inflammatory cytokine IL-17A, which helps in clearing Lm.⁴⁵ In adaptive immunity, Tregs act as dynamic “brakes” to amplify or suppress CD8⁺ effector T cell responses in a way most beneficial to the host. The regulation mediated by Tregs is dynamic and diverse.⁶² Dolina et al revealed the dynamic changes of Tregs and their different effects mechanism at various stages:⁶² on the first day of acute Lm infection, Tregs increase, rapidly activating the inhibitory mechanism mediated by CD73 to generate adenosine, which fine-tunes the activation of CD8⁺ T cells through cell contact-independent suppression, thus preventing immunopathological reactions.^49,63,64 This Treg-mediated inhibition is short-lived. Subsequently, on the third day of Lm infection, Tregs decrease, leading to the primary expansion of Lm-specific CD8⁺ T cells. By the seventh day of Lm infection, as Lm-specific antigens are cleared and CD8⁺ T cell accumulation reaches its peak, a specific group of Tregs appears, depending on cell contact-dependent cyclic AMP transfer, mediating T cell contraction and restoring internal balance. Mischo Kursar et al found that during secondary Lm infection, Treg cells can limit the expansion of memory CD8⁺ T cells.⁶⁵ Additionally, NK T cells can provide early protection by producing systemic IFN-γ, preventing intestinal Lm infection.⁶⁶

The α-Galactosyl ceramide (α-GalCer) can promote the presentation of Lm antigen on MHC class I molecules, activate invariant NK T cells (iNKT cells) and CD8⁺ T cells, promote a burst of cytokines and chemokines, and facilitate and regulate immune responses led by iNKT cells.⁶⁷

In recent years, there has been no major progress in the study of cellular immune responses against Lm, with more research focusing on Lm’s evasion mechanisms of cellular immunity and the development of bacterial tumor immunotherapy using Lm’s adaptive immune features. For example, Selvanesan et al found that vaccines using Lm as a vector can activate CD4⁺ T cells in mice for the treatment of pancreatic ductal adenocarcinoma.⁶⁸ Flickinger et al discovered that the immunodominant epitopes of Lm vectors can tightly bind to host MHC molecules, competitively inhibiting the presentation of cancer antigens.³ Clinical trials are also ongoing with Lm that can secrete tumor-associated antigens (TAAs) effectively treating tumor-related mice in vivo.

These studies all demonstrate the key role of cellular immunity in the resistance to Lm. Activation of iNKT cells and CD8⁺ T cells by glycolipid α-GC enhances host adaptive immune responses and regulates the expression of Lm surface protein InlB, providing new strategies for clinical defense against Lm infection.

Deng et al suggested that combining Lm-induced lifelong immune protection with newly developed therapies such as checkpoint blockade to develop live vaccines will have promising prospects,⁶⁹ suggesting that vaccine development using Lm as a vector may have huge potential in the future of anti-tumor field.

Humoral Immunity

As known, Lm is a typical intracellular bacterium, which can spread directly between cells without relying on extracellular humoral immunity, so the role of humoral immunity in resisting Lm infection is relatively small, and its mechanism is not clear. However, research has found that during the infection of Lm in mice, the host itself does not induce a strong antibody response, but the presence of certain antibodies can inhibit bacterial growth (Figure 3). ⁴⁵ In addition, the vaccine of Lm is related to humoral immunity of the host, and results have shown that the mRNA vaccine of some adjuvants such as α-GC, ISA61 VG, etc., has a synergistic protective effect against Listeriosis, and can also inhibit bacterial growth by activating or enhancing the cell-mediated immune pathways.^70,71

Despite the limited direct role of antibodies in clearing intracellular Lm, emerging studies highlight their synergistic potential in vaccine design. Recent work by Mayer et al (2022) identified that antibodies targeting Lm surface antigens can opsonize extracellular bacteria, enhancing phagocytosis by macrophages and DCs. This process indirectly promotes antigen presentation and CD8⁺ T cell priming, bridging humoral and cellular immunity.⁷²

Critically, conflicting evidence exists regarding the functional efficacy of anti-Lm antibodies. While some studies report antibody-mediated inhibition of bacterial adhesion to host cells, others suggest Lm evades neutralization through rapid intracellular translocation. This gap underscores the need to dissect antibody specificity (eg, anti-LLO vs anti-InlB) and their spatial-temporal roles in different infection stages.

Therapeutic implications are particularly promising in vaccine development. Memory T cell-based vaccines can be enhanced by incorporating humoral components. For instance, Selvanesan et al demonstrate that Lm-vectored vaccines expressing tumor antigens (eg, for pancreatic cancer) not only activate CD8⁺T cells but also elicit antigen-specific IgG responses, which reduce bacterial dissemination and prolong host survival.⁶⁸

Further, novel adjuvant technologies synergize B cell activation with iNKT cell-mediated immunity, as shown in recent mRNA-LNP vaccines. Meulewaeter et al (2024) reported that such formulations significantly boosted anti-Lm IgG2c and Th1-skewed memory responses, highlighting the potential of combinatorial approaches.⁷³

However, major knowledge gaps persist in clinical translation. For example, Flickinger et al revealed that immunodominant Lm epitopes may competitively inhibit tumor antigen presentation in cancer vaccines—a challenge requiring epitope engineering to optimize humoral-cellular crosstalk.³

Summary and Outlook

Listeria infection in human body can manifest in three different forms, including bacteremia, neuroinvasive Listeriosis, and maternal-neonatal infection.⁹ After infecting the human body, it triggers a series of immune responses and mechanisms, including innate immune response and adaptive immune response (Table 1). Various immune barriers, immune factors, and cells are activated in the process of combating Listeria infection (Table 1). Since Lm is a typical intracellular bacterium, cellular immunity plays an especially important role in resisting Listeria infection, while humoral immunity plays an important role in Listeria vaccine.

Table 1 Host Defense Effects and Mechanisms of Lm

As a conditional pathogen, Lm infection does not have a serious impact on most normal populations, but it can cause serious harm and even death to immunocompromised groups, especially pregnant women and newborns.⁷ Pregnant women can transmit Lm to their fetuses through the placenta,⁷⁴ increasing the risk of miscarriage, premature birth, and death.⁷⁵ Furthermore, the probability of postpartum infants developing neurological complications such as sepsis and meningitis will also significantly increase. Notably, Lm’s unique ability to induce potent CD8⁺T cell responses positions it as a promising vector for bacterial tumor immunotherapy. Clinical trials using Lm-secreting tumor antigens demonstrate its potential to remodel the tumor microenvironment via CD8⁺ T cell-dependent mechanisms.⁶⁹ Combining Lm-based vaccines with checkpoint blockade or metabolic modulators may unlock synergistic antitumor efficacy. In conclusion, deepening our understanding of Lm-host immune interactions will accelerate the development of targeted immunotherapies and next-generation vaccines, ultimately reducing the burden of Listeriosis in vulnerable populations. With the continuous in-depth research on Lm, targeted inhibitors are also continuously being developed, such as amentoflavone can effectively inhibit LLO pore formation etc.⁷⁶ Hopefully, these new targets can help in the development of immunotherapeutics, thus prolonging the survival period of immune cells during infection and enhancing the host’s ability to fight against bacteria. It is believed that the treatment methods for Lm will continue to be updated and improved in the future.