Human β defensins (HBDs) 1, 2, 3, and 4 have been found to have overlapping expression patterns. HBD1 is produced and expressed in the lung airway epithelia, which are in direct contact with ambient microflora ^[1][17]. Microbial compounds, such as lipopolysaccharide (LPS) and peptidoglycan, have been shown to increase HBD1 expression ^[2][32]. HBD’s have been detected in various organs other than the lungs, such as the heart, liver, lung tumor tissues, and stomach epithelial cells, even though their expression patterns overlap ^[3][4][33,34]. Furthermore, pathogen-derived compounds, cytokines, and chemokines produced by the immune system or injured cells all influence HBD expression ^[5][35]. It has been found that when immune cells are exposed to bacteria, LPS, IFN-γ, and IL-6, the expression of HBDs increases ^[6][7][36,37]. In recent studies, human defensins were reported to have antiviral activities against SARS-CoV-2 ^[8][38]. Additionally, HNP-1, retrocyclin, and human intestinal defensin5 were shown to reduce the viral infection by blocking the viral entry and were suggested as valuable therapeutic tools to combat SARS-CoV-2 infection ^[9][10][39,40]. Overall, defensins are reported to have antiviral activity against both enveloped and non-enveloped viruses via direct activity and indirectly via immunomodulatory activities ^[11][41].

The only cathelicidin generated by a vitamin-D-dependent antibacterial mechanism in humans is LL37 ^[12][13][42,43]. LL37, like defensins, is generated as a pre-propeptide in epithelial cells and is involved in the first immune response to a variety of infections ^[14][44]. Proinflammatory cytokines and growth hormones, such as the active form of vitamin D, regulate LL37 expression ^[15][45]. LL37 attracts neutrophils, monocytes, dendritic cells, and T cells, and it is quickly secreted by epithelial cells and leukocytes during infection in the airways ^[14][44]. LL37 increases the synthesis of IL-6 in human dendritic cells and acts as both an anti- and proinflammatory agent during the early stages of an infection’s immune response ^[16][46]. Individuals with cathelicidin-deficient neutrophils have been observed to be more susceptible to viral infections ^[14][44]. It recent studies, it has been shown that LL37 has direct activity against human rhinovirus and respiratory syncytial virus, and can protect against respiratory infections caused by these viruses in both mice and humans ^[17][18][47,48]. Interestingly, cathelicidins represent an inducible therapeutic target for fighting against viral infections.

Lactoferrin is an iron-binding glycoprotein found in breast milk, tears, vaginal secretions, gut-lining fluids, cervical mucus, saliva, and respiratory secretions. Lactoferrin, like other innate immunity proteins, is a cationic protein with antibacterial and anti-inflammatory effects ^[19][49]. Neutrophils secrete lactoferrin at the site of inflammation, which aids in host defense and immunological regulation at mucosal surfaces ^[20][50]. Lactoferrin has been shown to have potent antibacterial activity against clinical E. coli, S. aureus, and mucoid P. aeruginosa strains isolated from cystic fibrosis patients’ airways ^[21][51]. Next, lactoferrin has been shown to have synergistic antibacterial activities against bacteria when combined with other respiratory tract immune proteins, such as lysozyme and SLPI ^[22][52]. Lactoferrin has been shown to exhibit antiviral activity against a variety of viruses, including HIV, cytomegalovirus (CMV), and hepatitis B and C, and to have therapeutic promise when combined with interferon ^[23][24][53,54]. Lactoferrin has also been found to prevent inflammatory cells from infiltrating the lungs during pneumonia when taken orally ^[25][55]. Lactoferrin is a major inflammatory protein that has been shown to inhibit LPS-induced IL-8 production and peptidoglycan binding characteristics in human endothelial cells ^[26][56]. According to a recent study, lactoferrin consumption directly protects the host by inhibiting viral attachment and replication in the cell while also increasing systemic immune activities ^[27][57]. Conclusively, lactoferrin has potential antiviral and immunomodulatory properties to protect against respiratory viral infection and is suggested to be used as a nutraceutical ^[28][58]. Interestingly, lactoferrin confirmed to have protective effects and reduced respiratory tract infections in controlled randomized clinical trials via modulation of inflammation and immune response ^[29][30][59,60].

SLPI is a non-glycosylated protein that is expressed on the mucosal surface of epithelial cells in the respiratory system by macrophages, neutrophils, and mucosal epithelial cells. SLPI, as well as lysozyme, lactoferrin, and other innate immunity proteins found in respiratory and nasal secretions, is abundant in BAL ^[31][32][61,62]. The serine protease inhibitor SLPI also protects from neutrophil elastase, which is released by neutrophils during infection and inflammation ^[33][63]. SLPI is a multifunctional peptide that acts as an antibacterial, antiviral, and anti-inflammatory peptide ^[34][64]. In an immunoglobulin G (IgG) immune complex model of acute lung damage, SLPI is found to decrease neutrophil recruitment and thus inflammation in the lungs ^[35][65]. Prior treatment with SLPI effectively reduced inflammation in both the liver and the lungs of a mouse model of hepatic ischemia/reperfusion injury ^[36][66]. The inactivation of SLPI has also been linked to an increase in lung parenchymal inflammation, tissue destruction, and pneumonia ^[37][67]. The oxidative-stress-sensitive protein SLPI is found in respiratory cell linings, which have mechanisms to alleviate oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an oxidative stress regulator that also regulates SLPI expression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, has recently been shown to boost Nrf2 activity, and consequently, supplementation with SFNs results in increased SLPI secretion in the nasal mucosa ^[38][68].

Lysozyme is a basic antimicrobial protein that kills bacteria by disrupting the glycosidic connection between N-acetylglucosamine and N-acetylmuramic acid residues in peptidoglycan, which is a component of the bacterial cell wall. Both phagocytic and secretary neutrophils retain lysozyme, which is also generated by monocytes, macrophages, and the respiratory epithelium ^[39][69]. In the respiratory tracts of lysozyme-expressing transgenic mice, increased bacterial killing is observed. Furthermore, increased lysozyme concentration is found to link to lower systemic bacterial infection and increased in vivo survival ^[40][70]. It was demonstrated in a different in vivo study employing tracheal xenograft airways with or without submucosal glands that lysozyme secretary glands efficiently clear the bacterial load. Additionally, Immuno-depletion experiments revealed a strong antibacterial role for lysozyme in lung airways ^[41][71]. In a recent study, lysozyme was reported to have protective effects against SARS-CoV-2 in human corneal epithelial cells ^[42][72]. Interestingly, niclosamide-lysozyme particles were revealed to have potential anti-coronavirus activities and were suggested to develop as a therapeutic agent ^[43][73]. Overall, due to its potential antiviral activities and immunomodulatory properties, lysozyme is suggested as a promising therapeutic agent ^[44][74].

Lactoperoxidase (LPO) is a mammalian heme peroxidase that is released from the mucosal membrane of the airways and has been shown to reduce respiratory infections ^[45][30]. The presence of the LPO system and its role in the host defense has been investigated in human airways and tissue secretions ^[46][75]. LPO causes the oxidation of iodine, which is reported to increase the antiviral defense of respiratory mucosal surfaces ^[47][76]. Next, LPO-produced hypothiocyanite and hypoiodite were shown to have anti-influenza activity and suggested the development of an LPO-based antiviral system to protect against airway infections ^[48][77]. LPO is reported to combat the influenza virus in mice upon oral administration by reducing the infiltration of inflammatory cells in the lung ^[25][55]. Overall, LPO-based antiviral systems could be developed as an efficient alternative to combat respiratory viral infections to protect the lung airways.

Chemokine ligand 20 (CCL20) has an antiparallel sheet core structure, charge distribution, and adaptive immunological signaling via a highly selective CCR6 receptor, all of which have structural and functional parallels with HBDs. CCL20 has been found to have dual functions in innate and adaptive immunity and is regulated by inflammatory mediators expressed in the airway epithelium ^[49][31]. Neutrophils have been shown to create CCL20, which is controlled by inflammatory cytokines, such as IL-1 and TNF-, via the NFB pathway ^[50][51][78,79]. CCL20 levels were shown to be higher in cystic fibrosis patients’ BAL compared to healthy BAL, implying that CCL20 plays a function in the respiratory immune defense ^[49][31]. CCL20 was reported as having anti-HIV-1 activity in the human female reproductive system via direct interaction with the virus ^[52][80]. Furthermore, increased levels of CCL20 are found in COVID-19 patients when compared to healthy counterparts ^[53][81]. This suggested a possible virally induced expression regulation of CCL20, which could be therapeutically targeted to protect lung airways against respiratory viral infections.