Abstract
Inhalation is required for respiration and life in all vertebrates. This process is not without risk, as it potentially exposes the host to environmental pathogens with every breath. This makes the upper respiratory tract one of the most common routes of infection and one of the leading causes of morbidity and mortality in the world. To combat this, the lung relies on the innate immune defenses. In contrast to the adaptive immune system, the innate immune system does not require sensitization, previous exposure or priming to attack foreign particles. In the lung, the innate immune response starts with the epithelial barrier and mucus production and is reinforced by phagocytic cells and T cells. These cells are vital for the production of cytokines, chemokines and anti-microbial peptides that are critical for clearance of infectious agents. In this review, we discuss all aspects of the innate immune response, with a special emphasis on ways to target aspects of the immune response to combat antibiotic resistant bacteria.
Introduction
The lung is a warzone. The primary function – gas exchange, puts this internal organ in direct contact with the outside world. As such, the pulmonary epithelium is exposed to a daily onslaught of infectious agents, hazardous pollutants and toxic particles. While the lung has evolved many defensive mechanisms to maintain the epithelial borders, pneumonia remains the most common cause of hospitalizations in adults and it is the fifth cause of death in children 5–9 years old (Greenbaum et al., 2014). It is therefore imperative to understand the immune responses in this complex organ in order to help reduce infection and promote pulmonary well-being.
Abbreviated examples of innate immune system response in the respiratory epithelium interface to different types of pathogens.
(A) Influenza infection: viral particles in the airway lumen are detected by TLR3 and TLR7 in the epithelial cells, triggering an initial response by NF-κβ, activating Type I and II interferons, producing CXCL2 and other chemokines that attract effector cells like macrophages and T cells as well as cytokines, such as IL-1β, IL-17 and IL-18. (B) Klebsiella pneumoniae infection: this Gram-negative bacteria is sensed by TLR2 and TLR3, unfolding a signaling cascade by MyD88, TRIF and NF-κβ, this cascade results in chemokines such as CXCL1, CXCL2 and CXCL5, promoting the recruitment of immune cells and releasing cytokines, most notably, IL-17, IL-6 and TNF-α. (C) Aspergillus fumigatus infection: the airway epithelium detects connidia or hyphae by TLR-2, TLR4 and Dectin-1. Decting-1 activates PCK- , recruiting neutrophils and other immune cells that exert antifungal activity by NADPH and reactive oxygen species (ROS). TLR2 and TLR4 activate PI3K, MAPK and ERK1/2 which results in production of cytokines and chemokines such as IL-8, IL-1α, IL-1β, IL-17, TNF-α, CCL3, CCL4, CxCL1 from the epithelium and immune cells. This response not only contributes to the acute defense of the lung, but also further activate the adaptive immune response.
The scope of this article is to review the role of the innate immune system in combating respiratory borne pathogens and provide an update with the latest research in the field.
Epithelial cells and mucosal immunity
Barrier and mucosal immunity activities of the lung epithelium
The epithelium is the front line of defense against infection. The initial responsibility of the pulmonary epithelium is to act as a physical barrier between the lumen and vasculature. It does this through the formation of tight junctions involving claudins, occludins and adherens such as E-cadherin and β-catenin, among others (for an excellent review see Wittekindt, 2017). The integrity of the epithelial layer in the lungs and alveolar spaces is central to preventing infectious agents from colonizing and disseminating from the lung as well as preventing fluid build-up (edema) in the lung. Tight junction formation can be altered by viral infections that target the epithelium. The two most common are influenza, which impairs claudin-4 (Short et al., 2016) and respiratory syncytial virus (RSV) which downregulates the expression of occludins and claudin-1 (Kast et al., 2017). Bacterial infections such as Pseudomonas aeruginosa can also result in edema due to loss of zonula occludens-1 proteins (Higgins et al., 2016).
Pattern recognition receptors (PRRs)
Loss of epithelial integrity can have dire consequences, allowing dissemination of infectious agents into the blood stream while at the same time, letting fluid build-up in the lung and reducing gas exchange. It is therefore critical that the pulmonary epithelium monitor the apical surface for signs of infection. It does this through PRRs, which are integral to the innate immune response.
Human lung epithelium and innate immune cells express TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR8, TLR9 and TLR10, each recognizing different antigens (Table 1). In gene expression studies, it was found that dsRNA (such as in influenza infection), recognized by TLR3, was the most effective stimulus of airway epithelial cells, inducing a strong cytokine and chemokine response (Doyle et al., 2003; Sha et al., 2004). In contrast, the TLR2 and TLR5 response from alveolar macrophages elicits a more effective response against bacterial agents and allergens, promoting an enhanced response from the airway epithelium (Hess et al., 2010). TLR4 recognizes Gram-negative bacteria and can induce up-regulation of TLR3 in alveolar macrophages (Ding et al., 2017). Clinically, this can result in elevated viral susceptibility due to synergistic amplification, triggering an exacerbated inflammatory response during subsequent viral infections. This is important because patients surviving severe bacterial pneumonia can have extensive tissue damage or even death in secondary viral infections (Ding et al., 2017).
Human TLRs and their ligands.
| TLR | Ligand |
|---|---|
| TLR1 | Triacyl lipoproteins |
| TLR2 | Peptidoglycans and heat shock proteins, lipoprotein and high mobility group 1 (HMGB1) amphoterin, lypotechoic acid, zymosan. |
| TLR3 | dsRNA (self and viral) |
| TLR4 | Heat shock proteins, LPS, RSV fusion protein, fibrinogen, fibronectin, heparan sulfate, hyaluronic acid, mouse mammary tumor virus envelope, HMGB1. |
| TLR5 | Flagellin |
| TLR6 | Lypotechoic acid, zymosan, triacyl lipoproteins |
| TLR7 | ssRNA (self and viral) |
| TLR8 | ssRNA (self and viral) |
| TLR9 | DNA (self, viral and bacterial) |
| TLR10 | Unknown |
The function of TLRs is to induce inflammation that can lead to clearance of the infectious agent. However, TLRs can also be immunosuppressant, depending on context. For example, LPS along with certain growth factors, such as vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) and cytokines like interleukin (IL)-1β, IL-6, can induce myeloid-derived suppressor cells in the lungs, that exert an anti-inflammatory response and limit inflammation-derived tissue damage (Ray et al., 2013).
The importance of TLR signaling in response to infection make them attractive therapeutic targets. According to the National Institutes of Health (NIH), there are 48 clinical trials exploring TLR activation as targets for cancer, metabolic disorders and infectious diseases (https://clinicaltrials.gov). For example, the synthetic molecule PUL-042 targets TLR2 and TLR9, enhancing their effects on innate immune response. In a model of influenza infection in mice, oseltamivir, a common drug used to treat influenza A, was given in combination with PUL-042, improving the rate of survival after receiving lethal doses of influenza A (Leiva-Juarez et al., 2018). TLRs are also being used as potential adjuvants to increase vaccine efficacy. The combinatorial stimulation of TLR4 and NOD2 can enhance the cellular and humoral response when used in vaccines (Tukhvatulin et al., 2016). The concomitant activation of TLR1/2, TLR3, TLR4 and NOD1 can augment the inflammatory response to asthma and infections after stimulation with their agonists such as Pam3CSK5, LPS, poly (I:C), R-837 and iE-DAP, promoting the release of IL-6, IL-8, GM-CSF, ICAM1, RANTES and HLA-DR (Månsson Kvarnhammar et al., 2013). In Table 2, we summarize the clinical trials pertaining to infectious diseases in the lung.
Clinical trials using TLR to address lung infections.
| Title | Conditions | Interventions | Locations | URL |
|---|---|---|---|---|
| Enhancing influenza vaccination in seniors with TLR (Toll like receptor) agonists | Influenza Vaccination in Seniors | Drug: resiquimod | Drug: placebo gel | University of British Columbia, Vancouver General Hospital, Vancouver, British Columbia, Canada | https://ClinicalTrials.gov/show/NCT01737580 |
| Toll-like receptor 2 gene polymorphism, serum cytokines and susceptibility to disease severity or treatment response of pulmonary tuberculosis | Pulmonary tuberculosis| genetic variants of host|immune response of host | Kaohsiung Chang Gung Memorial Hospital, Kaohsiung Hsien, Taiwan|Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan | https://ClinicalTrials.gov/show/NCT00772408 | |
| Possible relation of Toll-like receptors and Nitric oxide to chronic lung disease | lung diseases | Procedure: tracheal aspirate fluid | Children’s Mercy Hospital & Clinic, Kansas City, MO, USA|Children’s Hospital and Regional Medical Center (Seattle), Seattle, WA, USA | https://ClinicalTrials.gov/show/NCT00245167 |
| Ventilator-associated pneumonia (VAP) in intensive care unit (ICU) | Ventilator-associated pneumonia | Zakynthinos, Larisa, Mezourlo, Greece | https://ClinicalTrials.gov/show/NCT00935285 | |
| Innate immunity and respiratory syncytial virus (RSV) infection in children | Respiratory syncytial virus infection | University of Wisconsin-Madison, Madison, WI, USA | https://ClinicalTrials.gov/show/NCT00593918 | |
| Immune response to Toll-like receptor 9-agonist adjuvanted pneumococcal vaccination in HIV infected adults | HIV Infections | Biological: Pneumococcal vaccines + CPG 7909|Biological: pneumococcal vaccines | Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark | https://ClinicalTrials.gov/show/NCT00562939 |
| Intradermal influenza vaccine in the young | Influenza viral Infections | Drug: Imiquimod ointment|Drug: aqueous cream|biological: intradermal influenza vaccine|biological: Intramuscular influenza vaccine | The University of Hong Kong, Queen Mary Hospital, Hong Kong, China | https://ClinicalTrials.gov/show/NCT02103023 |
| Safety and immunogenicity of VAX125 influenza vaccine in community-living adults >=65 years of age | Influenza | Biological: VAX125 | JCCT, Lanexa, KS, USA|University of Rochester, Rochester, NY, USA|Coastal Carolina Research Center, Charleston, SC, USA | https://ClinicalTrials.gov/show/NCT00966238 |
| Multi-drug resistant tuberculosis in Korea | Tuberculosis | National Masan Tuberculosis Hospital, Clinical Research Center, Masan, Republic of Korea|National Medical Center, Seoul, Republic of Korea | https://ClinicalTrials.gov/show/NCT00341601 |
Another type of PRRs are the NOD-like receptors (NLR). The main NLRs are NLR3 and NLR4. NLRs form inflammasomes, which are multimeric proteins regulating caspase-1 activity and triggering inflammation via IL-1β, and IL-18 (Guo et al., 2015). During infection, inflammation is a helpful mechanism for microbial clearance. However, inflammasome activation and the subsequent release of IL-1β also have deleterious effects on the local tissue through the recruitment and activation of neutrophils (Ceballos-Olvera et al., 2011; Rathinam et al., 2012). NLRs are important in limiting infections. NLR4 is a potent inducer of pyropoptosis, limits bacterial intracellular growth (Ceballos-Olvera et al., 2011) and is important in the clearance of multiple bacterial infections including Salmonella typhimurium, Shigella flexneri, P. aeruginosa and Burkholderia pseudomallei (Chiang et al., 2018). NLRs are also the link between intestinal commensal flora and early innate response to infections in the lung, as demonstrated in a study where depletion of gut microbiota, but not upper respiratory tract commensals impaired early innate clearance of Klebsiella pneumoniae infection via NLRs (Clarke, 2014).
Mucins as defense mechanisms
Mucins are extracellular proteins produced primarily by goblet cells and club cells (Fahy and Dickey, 2010), as well as pseudostratified columnar ciliated cells throughout the airway epithelium. The most common mucins in the lung are MUC5AC and MUC5B which play important roles in defensive barrier function as a component of the viscous mucus that covers the ciliated structures in the airway (Thornton et al., 2008; Kim, 2012).
During the acute inflammation phase of viral and bacterial infections, tumor necrosis factor (TNF)-α, up-regulates MUC1 production promoting resolution of inflammation by inducing IL-10 production in dendritic cells (Li et al., 2010; Choi et al., 2011). Despite its antimicrobial affects, certain bacteria have developed mechanisms to overcome mucin. Pseudomonas aeruginosa can bind to MUC1 (Kim, 2012) and modulate inflammatory responses by reducing the phagocytic activity of classically activated (M1) macrophages (Kato et al., 2017a,b), contributing to microbial resistance by hijacking part of the host’s innate immune response.
Antimicrobial peptides (AMPs) and other immunoregulatory peptides
AMPs were initially discovered and named for their direct antimicrobial properties (Zasloff, 2002). They are abundantly produced in the lung, where they act as a first line of defense against infection. Defensins (alpha and beta), LL-37, RegIIIγ and surfactant proteins are examples of predominant AMPs in the lung.
Defensins alpha and beta, are produced primarily by neutrophils and epithelial cells in humans. In mice, alpha-defensins are found in Paneth cells, but not in neutrophils (Eisenhauer and Lehrer, 1992). Early studies determined that alpha defensins have a potent anti-viral action by directly binding to viral particles, impairing their ability to infect cells (Daher et al., 1986; Wilson et al., 2013). Beta-defensins also possess chemokine activity, indirectly enhancing the immune response against infections by inducing the production of MCP-1, Gro-α and monocyte-derived chemokine (MDC) from monocytes (Petrov et al., 2013). Beta-defensins have been a focus of intense study due to their roles not only as antimicrobial agents but also as immunomodulators. In this context beta-defensins have a pro-inflammatory effect, acting as chemoattractants to T cells, immature dendritic cells and macrophages (Semple and Dorin, 2012). Beta-defensin can be induced directly by P. aeruginosa (Scharf et al., 2012), whereas during Brucella abortus infection, it is indirectly induced by infected monocytes production of IL-1β (Hielpos et al., 2015).
LL-37 is a member of the cathelicidin family and is produced by epithelial and myeloid cells (Dürr et al., 2006). In humans, LL-37 can inactivate LPS and possesses direct antimicrobial effects by disrupting the bacterial membrane (Choi et al., 2017). It also stimulates epithelial cell release of IL-8 and transactivation of epithelial growth factor receptor (EGFR) (Sandra Tjabringa et al., 2005). CRAMP (cathelicidin-related AMP), the murine orthologue, plays an immunomodulatory role during bacterial sepsis through the reduction of TNF-α and nitric oxide production, as well as serving as a chemoattractant (Cirioni et al., 2006). Because of these properties, LL-37 has been actively studied as a potential therapeutic agent in sepsis (Bowdish et al., 2005; Cirioni et al., 2006).
Another important antimicrobial peptide is RegIIIγ, a C-Type lectin AMP that specifically targets Gram-positive bacteria. In the adult lung, RegIIIγ is induced in a STAT3 dependent manner and is critical for the clearance of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia (Choi et al., 2013). Interestingly, neonates have reduced expression of RegIIIγ, contributing to the susceptibility of infection and impairment of MRSA clearance (Fitzpatrick et al., 2017).
In the airway, surfactant proteins A (SP-A) and D (SP-D) are part of the collectin AMP family (Coya et al., 2015). Pathogens interact with the leptin domain of collectins, resulting in opsonization and subsequent phagocytosis (Wright, 2005). Unlike SP-A, SP-D has a strong antiviral response to influenza and has been suggested as a possible therapy to enhance mucosal immunity during influenza outbreaks (Hillaire et al., 2014), or as a biomarker due to its elevated serum levels during certain acute and chronic infections (Gaunsbaek et al., 2013; Güzel et al., 2014). Surfactant protein C (SP-C) is less characterized, but it has been shown to have immunomodulatory effects via JAK/STAT activation in lung repair after ARDS (Jin et al., 2018).
Lipocalin-2 is a siderophore binding AMP required for the clearance of K. pneumoniae (Chan et al., 2009) and Streptococcus pneumoniae (Warszawska et al., 2013). However, lipocalin can suppress macrophage activation and impairing bacterial clearance. Furthermore, the higher the levels of lipocalin-2 correlate with worse outcomes in pneumococcal infection (Warszawska et al., 2013). Similarly, in a sepsis model, high levels of lipocalin-2 expression in lung tissue were observed in C57BL/6 J mice, but not in A/J mice, suggesting that differential genetic background in IL-10 production by macrophages, which regulates lipocalin-2 expression might play a role in the severity of sepsis and could be used as a prognosis marker (Vazquez et al., 2015).
Complement
The complement system are plasma proteins that function as key effectors in the immune response against pathogens by enhancing phagocytosis, production of active mediators of inflammation like C5a and C3a and by attacking the pathogen’s cell membrane. Most of the complement proteins are made by hepatocytes, but can also be produced by circulating monocytes, tissue macrophages and epithelial cells in the lung. Complement circulates as inactive proteins, but can be activated by three different pathways, classical, alternate and leptin.
Hyper-activation of complement can result in tissue damage. For instance, it has been reported that H5N1 avian influenza causes excessive activation of complement causing acute lung injury (Sun et al., 2013) leading to acute respiratory distress syndrome (ARDS). Inhibition of complement activation in this model helps alleviate lung injury (Sun et al., 2013). In a model of Mycobacterium tuberculosis component factor C7 contributes to lung injury and bacterial persistence by promoting the formation and maintenance of granulomas (Welsh et al., 2012). The modulation of the complement system is an active field of research in inflammation-related tissue damage. Interestingly, alpha-defensins can modulate complement by inhibiting its production (Hiemstra, 2015).
Cellular immunity, components and effectors
Cellular immunity is central to the innate immune response in the lung where resident immune cells monitor and maintain homeostasis as well as cells that emigrate to the tissue when activated by infection or tissue damage. The main components of cellular immunity are macrophages, monocytes, dendritic cells, neutrophils and innate immune cells. For examples and summary of the innate response during infection by three different pathogens, see Figure 1.
Monocytes and macrophages
Macrophages are the central innate cellular response to infection. They kill directly by phagocytizing infecting agents, while recruiting other immune cells through the release of multiple cytokines and chemokines. Following insult, circulating monocytes differentiate into macrophages or dendritic cells (DCs) to exert their innate immune response in the lung tissue. In contrast, tissue resident macrophages are already in the lung. These first responders play important roles in immunomodulation, tissue repair and homeostasis in the lung after microbial clearance. Lung macrophages are commonly divided in two groups: alveolar macrophages (AM) and interstitial macrophages (IM). For a detailed description of how these cells are characterized, see Kopf et al. (2014). While research suggests macrophages can exist in a transient state from one type to another, both AMs and IMs play important roles in homeostasis and host protection (Sugimoto et al., 2015).
Alveolar macrophages patrol the alveolar surface and are generally the predominant immune cell in a healthy lung. These cells develop during the first week after birth from fetal monocytes that populate the lung during development (Guilliams et al., 2013; Gomez Perdiguero et al., 2015), and are able to self-replenish with very little contribution from circulating monocytes (Yona et al., 2013). Most AM are polarized towards an anti-inflammatory phenotype called M2 and collaborate in lung development in newborns (Jones et al., 2013).
AMs have varying roles in response to viral infection, depending on the agent. During RSV and influenza infection, AMs promote viral clearance (Wang et al., 2012; Eichinger et al., 2015). While influenza clearance requires the production of high amounts of type I and type III interferons (Wang et al., 2012), AMs suppress RSV replication independent of interferon production (Makris et al., 2016).
Interestingly, AMs are not always beneficial. During human metapneumovirus (hMPV) infection, AMs contribute to lung pathology by facilitating early entry and replication in the lung, as well as production of inflammatory soluble factors (Kolli et al., 2014). Further, AMs are potential HIV-1 reservoirs in otherwise healthy patients with undetectable plasma viral loads, which impairs AMs phagocytic function making these patients more susceptible to respiratory infections (Cribbs et al., 2015). In tuberculosis, low genetic expression of macrophage migration inhibitory factor (MIF) is a risk factor for certain populations due to a decreased ability to manage early infection and dissemination of mycobacteria (Das et al., 2013). This phenomenon highlights the seemingly opposing roles for the innate immune system.
IMs are also believed to have homeostatic functions and defend against pathogens (Sugimoto et al., 2015). In contrast to AMs, proliferation of IMs is high when stimulated with LPS or IFN-γ, but are shorter lived (Sugimoto et al., 2015), suggesting that IMs have an important role in innate immunity in the lungs.
In general, it has been proposed that AMs are central in pathogen clearance, whereas IMs play a greater role in immunomodulation of the adaptive response due to their higher expression of MHCII (Steinmüller et al., 2000). However, in some infections, IMs play a key role in clearance. IMs are important in Chlamydia muridarum infection, where the pathogen targets IMs for infection, thus activating them. Upon IM activation, an IFN-γ induced cytokine response promotes pathogen clearance, suggesting that imbalances in the different macrophage populations can lead to C. muridarum associated pathology (Gracey et al., 2015).
Similar to macrophages, circulating Monocytes also have antimicrobial functions. Monocytes expressing CCR2 and Ly6C as well as monocyte-derived DCs have a pivotal role in conidial clearance during A. fumigatus infection indirectly by recruiting neutrophils that will attack conidia and directly by ingesting conidia during the process of DC differentiation, resulting in direct conicidial activity (Espinosa et al., 2014).
Dendritic cells
Lung DCs serve as sentinels against infections, representing the interface between innate and adaptive immune response (Belz et al., 2004; Condon et al., 2011). Plasmacytoid DCs play a central role in viral infections such as RSV or H1N1, eliciting a type I interferon protective response, activating the adaptive immune machinery (Garg et al., 2012; Cormier et al., 2014). Although, in certain highly pathogenic influenza strains, it is suggested that the increased amount of DC recruitment may contribute to the pathogenicity of the strain (Soloff et al., 2014). Recently, researchers are also focusing on DCs participation in bacterial infections. For instance, there is active research on the role of plasmacytoid DCs against early stages of Chlamydia pneumoniae, where they promote an innate pro-inflammatory state in the lung but have a suppressive role in the lymph node (Crother et al., 2012).
Neutrophils
Neutrophils are part of the early innate immune response. In humans, they are the most common white blood cell in the circulation. During infection, neutrophils respond to chemokines (IL-8, MIP-1) and travel to the site of inflammation. Lung migrating leukocytes do not use the usual rolling and tethering that is required in other peripheral organs for extravasation, allowing higher neutrophil concentration in the lungs during inflammation (Burns et al., 2003). Confocal microscopy studies have demonstrated that pericytes, contractile cells found around the endothelium of capillaries, assist in the process of neutrophil transmigration (Proebstl et al., 2012).
Neutrophils exert direct and indirect antimicrobial effects during the innate immune response to infection. They directly kill the infecting agent by phagocytosis, by creating neutrophil extracellular traps (NET) or through activation of other innate immune cells, like macrophages. For example, it has been reported that neutrophils are required for macrophage activation against helminth Nippostrongylus brasiliensis infection, accelerating clearance (Chen et al., 2014). Neutrophils also participate in the clearing of Aspergillus fumigatus hyphae through myeloperoxidase and NADPH oxidase and conidia through lactoferrin-mediated iron sequestration (Garth and Steele, 2017). Recent reports have postulated that Dectin-1 and Mac-1 induced activation of PKC-γ is key to fungal clearance because it is required for reactive oxygen species production upon cellular uptake (Li et al., 2016). Because of their relevance in infectious and autoinflammatory diseases, neutrophils have become an interesting target for therapy. It has been found that CCR5 and FPR1 are required for neutrophil recruitment and blocking these molecules could be advantageous in limiting acute lung injury during bacterial pneumonia (Grommes et al., 2014). Neutrophil recruitment in bacterial clearance requires the action of chemokines CXCL5 and CXCL1, which are activated via IL-17/IL-17R axis (Chen et al., 2016). Furthermore, it has been suggested that neutrophil recruitment and damage in the lung is a dysregulation of the CXCL1/CXCR2 at the target tissue (Sawant et al., 2015).
Innate lymphoid cells (ILCs)
ILCs are recently described tissue resident T-cells. In 2013, Spits et al. proposed a nomenclature for ILCs, categorizing them in three groups based on the cytokines and transcription factors they produce (Spits et al., 2013). NK cells and ILC1 make up Group I. Group I cells produce IFN-γ and TNF. ILC2 are the only member of Group 2. Upon activation by IL-33 and IL-25, ILC2 are the main producers of IL-4, IL-5, IL-9, IL-13 and AREG (Ebbo et al., 2017; Richards, 2017). NCR+ILC3, NCR-ILC3 and LTi cells are all part of Group 3, which produce IL-17, IL-22 and IFN-γ (Spits et al., 2013). Although there are similarities with conventional T-cells, they play different roles in immunity, tissue remodeling and development (Ebbo et al., 2017). ILCs are unique in that they lack RAG genes but share TCR signaling molecules such as ICOS, LAT and LCK (Paclik et al., 2015). This allows them to be non-specifically activated, as they lack antigen-specific receptors (Spits et al., 2013; Mjösberg and Spits, 2016). However, ILCs are capable of presenting antigens to T-cells during bacterial and parasitic infections (Hepworth et al., 2013; Oliphant et al., 2014). Despite the proposed classification, ILCs have plasticity, which makes them change their phenotype upon challenges in the microenvironment (Silver et al., 2016).
An important subgroup of ILC1, NK cells, are an important player during control of cancer development and certain infectious diseases due to their cytotoxic activity. During Toxoplasma gondii infection (Dunay and Diefenbach, 2018), NK cells are the major source of the anti-inflammatory cytokine IL-10 (Wagage et al., 2014) or in response to other pathogens, IFN-γ (Richards, 2017). In response to K. pneumoniae pneumonia, NK cells orchestrate the innate immune response by producing type I interferons, which in turn activate alveolar macrophages to exert their protective role in the infected lung (Ivin et al., 2017). NK cells have also been demonstrated to be essential for the control of murine cytomegalovirus acute stage of infection, underlining its well-known role in viral infections (Andrews et al., 2003). Despite the classification proposed by Spits, under certain circumstances, ILCs can produce cytokines that do not fit within his typical nomenclature. For example, during influenza pneumonia NK cells produce IL-22, which is an important cytokine primarily involved in repair and tissue regeneration (Pociask et al., 2013; McAleer and Kolls, 2014). ILC2s have been associated with lung protective effects during viral infection, particularly during influenza by producing amphiregulin, which helps with tissue regeneration (Monticelli et al., 2011; Califano et al., 2018).
Since the characterization of ILCs, it was thought that ILC1 and ILC2 are the only groups found in the lung. However, several studies have found that ILC3 is also present in the mouse lung (De Grove et al., 2016). Many of these studies are in the context of cancer, where ILC3s are linked to the production of IL-22, TNF-α, IL-8 and IL-2, and contribute to the formation of tertiary lymphoid structures, eliciting a protective role in cancers (Carrega et al., 2015; Ferlazzo et al., 2016). Some studies have also found ILC3s in the context of allergy and helminthic infections in the lower respiratory tract (Taube et al., 2011; Tait Wojno and Artis, 2016). A recent study by Gray et al., found that in the lungs of newborn mice there is a large population of ILC3 cells. These cells are proposed to migrate during early stages of development from the small intestine to the lung, where they are crucial in the resistance to pneumonia in the newborn mice (Gray et al., 2017), connecting the gut microbiota and mucosal immunity with lung innate immunity.
T cells
Some immune cells, like the T helper type 17 (Th17) cells produce cytokines that not only are relevant in the immune innate response to infections in the lungs, but also promote the integrity of the epithelium by promoting proliferation of epithelial cells. The cytokines IL-17A and IL-22 are crucial in the homeostasis and tissue repair. As part of the mucosal immunity, IL-17A and IL-22, produced by CD4 T cells, are associated with innate defense in K. pneumoniae pneumonia (Aujla et al., 2008).
γδ T-cells are a subset of T cells that have innate immune cell properties and thought to act as a bridge between the innate and adaptive responses. They migrate to mucosal surfaces early in development and are considered a tissue resident T cell. γδ T-cells are critical in clearing many infections. In Pneumocysti carinii infection, γδ T-cells modulate host’s susceptibility due to their interaction with CD8+ T cells and local production of IFN-γ (Steele et al., 2002). In M. tuberculosis infection they produce IFN-γ that triggers macrophages to produce nitric oxide as a defense mechanism (Pahari et al., 2018). Enhancing the γδ T-cell population and promoting their activation is under study as a viable approach for the development of tuberculosis vaccines (Xia et al., 2016). In other bacterial infections, such as K. pneumoniae, γδ T-cells are required for TNF-α and IFN-γ production and bacterial clearance and survival (Moore et al., 2000), making these cells a critical component of the innate immune system.
Inducible structures
Following an infection, inflammatory cells may persist in the lung and can form tertiary lymphoid structures. These structures are categorized by the cellular make up. The two most common inducible pulmonary lymphoid structures are granulomas and inducible brochus-associated lymphoid tissue (iBALT). These structures form to contain pathological agents or to help promote localized immunity to other infections.
Granulomas are commonly formed through infection by fungi and mycobacteria such as M. tuberculosis (TB). The TB granuloma is formed by macrophages and T cells that surround the mycobacteria, creating a pathogen-host interaction. These granulomas vary in general composition but must maintain a balance between pro-inflammatory and anti-inflammatory to protect from the bacteria getting out (Gideon et al., 2015). However, the pro-inflammatory and antimicrobial effects in the granuloma are not just based on cytokines, but also in antimicrobial peptides (AMPs) and reactive oxygen species (ROS). A recent proteomic study of the spatial distribution in granulomas revealed that the necrotic center contains a highly pro-inflammatory environment with high levels of AMPs and ROS, as well as pro-inflammatory cytokines like IFN-γ, whereas the surroundings tend to be anti-inflammatory, hypothesizing that such distribution is relevant to contain the pathogen while limiting tissue destruction (Marakalala et al., 2016).
Another inducible structure is the induced iBALT. This structure is composed of B and T cell zones, dendritic cells as well as high endothelial venules and lymphatics (Moyron-Quiroz et al., 2004). These structures contain antigen presenting cells that generate memory T and B cell responses in response to subsequent infection promoting a rapid, focal response to secondary infection (Moyron-Quiroz et al., 2004, 2006; Halle et al., 2009). iBALT formation occurs in response to a number of bacterial and viral infections (Hwang et al., 2016) and is dependent upon the production of IL-17 (Rangel-Moreno et al., 2011) and requires a number of chemokines such as CXCL13, CCL19 and CXCL21 (Rangel-Moreno et al., 2007).
Summary and outlook: innate immunity and antibiotic resistance
Antibiotic resistance is a major public health problem although many new drugs are being discovered. Unfortunately, resistance to those drugs quickly develops, raising concerns about new treatments and management. Multi-target mechanisms, targeting virulence factors as well as several steps in the same pathway, could enhance the innate immune response (Oldfield and Feng, 2014). Many have proposed using AMPs as alternatives to conventional agents to mitigate antibiotic resistance. While bacteria can develop resistance to AMPs, they retain the ability to enhance the innate immune response (Andersson et al., 2016). While direct administration of AMPs is an attractive therapy, concerns of toxicity (Falagas et al., 2006) and efficacy have limited this approach to mostly topical applications (Andersson et al., 2016). Therefore, alternative approaches that locally induce AMPs at the site of infection may be a safer therapy.
Cytokine administration may offer a more practical therapeutic approach. A number of cytokines can induce AMPs in localized areas of infection and injury. IL-22 is once such cytokine. It is not only critical for protection of pulmonary epithelium during infection (Kumar et al., 2013; Pociask et al., 2013) it induces production of lipocalin (Aujla et al., 2008) and RegIIIγ (Barthelemy et al., 2018) which are critical for clearance of Gram-negative bacteria (Aujla et al., 2008) and protection from secondary bacterial infection (Barthelemy et al., 2018). It also induces complement (C3) which aids in the clearance of pneumococcal pneumonia (Trevejo-Nunez et al., 2016).
Certain drugs can also have indirect or secondary antimicrobial properties through increased AMPs, thus increasing innate immunity. For example, statins promote the formation of extracellular traps, although they also have a negative impact in oxidative stress formation and phagocytosis (Chow et al., 2010). It has been demonstrated that by targeting a step in in the sterol pathway has the effect of boosting the production of neutrophil and macrophage extracellular traps (NETs and METs) and AMP LL-37 (Liu et al., 2008; Chow et al., 2010; Lin et al., 2012), showing a protective effect of statins to S. aureus pneumonia.
In a different study, it was found that the administration of picostin, a molecule similar to the isoprenoid metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) in combination with IL-2, elicited an expansion of Vγ2Vδ2 T cells. This expansion conferred protection against tuberculosis-related lesions following mycobacterial infection, helping to reduce bacterial burden (Chen et al., 2013). Interestingly, a bioengineered vaccine providing HMBPP as a booster expanded γδ T cells subsets which effectively increased early innate response against S. typhimurium (Workalemahu et al., 2014).
While many studies aim to affect the T-cell compartment, increasing macrophage activation and killing have also been studied. Delivery of lipids in apoptotic body-like liposomes can promote phagosome activation and maturation, increasing intracellular killing of BCG through acidification and reactive oxygen species generation. This approach has also been used against P. aeruginosa conferring a higher capacity to innate system to handle drug resistant infections (Poerio et al., 2017).
Other methods have been developed that do not rely on AMPs. An example of this is the use chimeric proteins derived from domains 6 and 7 of human complement factor H fused with the IgG Fc domain. In this approach, the alternative pathway of the complement system is uninhibited, resulting in bacterial clearance by opsonization and subsequent phagocytosis (Blom et al., 2017). This was tested in models of infection with Haemophilus influenzae, Neisseria meningitidis and Neisseria gonorrhoeae with similar bactericidal effects (Shaughnessy et al., 2016; Wong et al., 2016). Another area of research is the use of peptidoglycan recognition proteins (PGRP). These proteins can contribute to limit infections by three potent bacteriostatic effects: oxidative, thiol and metal stress that combined become bactericidal, resulting in death of bacteria exposed to it. Also, it has been established that PGRPs provide enhanced innate immune responses as well as complement-dependent responses, such as phagocytosis and AMP production (Dziarski and Gupta, 2018).
Funding source: National Heart, Lung, and Blood Institute
Award Identifier / Grant number: 1RO1HL122760-01
Funding statement: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Funder Id: 10.13039/100006492, Grant Number: 1R21AI117569-01A1. National Heart, Lung, and Blood Institute, Funder Id: 10.13039/100000050, Grant Number: 1RO1HL122760-01.
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