4 TM for anti-MRSA infection
TM has exerted its unique efficacies in inhibiting MRSA infection[6, 12]. However, the bacteriostatic ability of TM is weaker than that of antibiotics.TM regulation of the body’s immunity might be a promising strategy to combat MRSA infection. In TM, single herbs and their active components as well as formulae play a key role in regulating host immunity. The mechanisms of these herbs and formulae were systematically analyzed and summarized (Table 3, Fig. 2).
4.1 Single Herbs and active components
4.1.1 Glycyrrhiza glavra (Glycyrrhiza polysaccharides)
Glycyrrhiza glavra (G. glavra , licorice) is an herbal medicine with various bioactivities. It has been used to treat lung injury and bacterial infection [65]. Its components including glycyrrhizin (GL) and its hydrolysis product 18-β-glycyrrhetinic acid (18-β-GA), as well as licorice flavonoids, can restrain bacterial infection [65]. GL has anti-inflammatory and immunomodulatory activities[66]. Neutrophils are its primary targets. By down-regulating the expression of endothelial adhesion molecules in neutrophils (ICAM-1 and P-selectin), GL prevents neutrophil adhesion, partly curbing local injuries [67]. It also decreases myeloperoxidase (MPO) levels. MPO, an enzyme mainly stored in azurophilic neutrophil granules, has potent antibacterial activity, and it is a marker of neutrophil migration and infiltration, as well inflammation and tissue injury [66, 68, 69]. GL can inhibit neutrophil phagocytosis, and it can treat the initial phase of lung inflammation. It decreases the secretion of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines (TNF-α, IL-1α, IL-6) by regulating NF-κB signaling molecules[66]. Both iNOS and COX-2 are induced by inflammatory stimuli and play important roles in MRSA pneumonia[70]. Altogether, GL inhibits MRSA pneumonia in the initial phase, mainly by preventing the adhesion, migration, recruitment, infiltration and phagocytosis of neutrophils.
18-β-GA can combat MRSA immune evasion and improve host immunity[71]. It markedly reduces MRSA immune evasion to alleviate infection via down-regulating the key virulence factors, saeR, hla, RNAIII, mecA, and sbi [72]. Additionally, it can regulate the functions of neutrophils and DCs. In a mouse model of MRSA skin infection, 18-β-GA reduces neutrophil recruitment by down-regulating KC and granulocyte colony-stimulating factor (G-CSF) to alleviate skin infection [72]. It also activates adaptive immune responses to anti-MRSA infection by targeting DCs[73]. In a mouse model of lipopolysaccharide (LPS)-induced inflammation, at doses of 1 mg/mL and 10 mg/mL, 18-β-GA increases CD40 expression levels in DCs [73]. The interaction of CD40 and its ligand CD40L can promote T cells activation and inflammatory cytokine (IL-1, IL-6 and IL-12) production and induce DC maturation and activation, thereby promoting immune responses[73].18-β-GA modulates the Th1/Th2 response through up-regulating Th1 responses. During the Th1 response, it also enhances the secretion of IL-10 by CD4+ T cells, and IL-10 limits Th1 responses in a regulatory-feedback loop [73, 74]. This process suggests that 18-β-GA may suppress excessive inflammatory-responses or terminate immune responses after pathogen eradication by upregulating IL-10. These results shed new light on the possibilities of exploiting these herbs and compounds for the treatment of infectious diseases by regulating DC maturation and T-cell differentiation. Besides its single use, GL exerts synergistic effects when combined with antibiotics. Licorice flavonoids can increase the sensitivity of MRSA strains to oxacillin, a β -lactam antibiotic[75].
4.1.2 Panax ginseng (Ginseng polysaccharide)
Panax ginseng (Pg) is known for invigorating and maintaining physical vitality [76]. Pg contains ginsenoside, polysaccharides and peptides. It exerts antibacterial and immunoregulatory functions and has been widely used for the treatment of infectious diseases [76]. Heat-processed Pg (at 100 °C) enhances the antimicrobial activity against S. aureus , which is due to increased levels of the ginsenoside Rg3, a major compound against S. aureus infection [77]. HPLC analysis shows that Rg3 penetrates the bacterial cell membrane more easily than other compounds, thereby inhibiting bacterial growth[77, 78]. Pg is an adjuvant for pneumococcal vaccines, which can enhance vaccine efficacy and increase the survival rate after lethal bacterial challenge [79]. Pg extracts and Rb1 ginsenosides also show an adjuvant effect on immunization against MRSA. Rb1 can promote both lymphocyte proliferation and antibody production specific for MRSA antigens[80].
Ginsan is a polysaccharide extracted from Pg [81]. It can protect mice from S. aureus -induced sepsis by bidirectionally modulating the IIS, mainly phagocytosis. It suppresses MRSA-induced sepsis by increasing the bactericidal activity of macrophages by increasing nitric oxide (NO) levels. Moreover, it restricts excessive inflammation by suppressing TLR2, TLR4, TLR9 and MyD88 levels, decreasing related downstream molecule (p38 MAPK and JNK1/2) phosphorylation, and reducing NF-κB activation and inflammatory cytokine (TNF-α, IL-1β and IL-6) levels. In conclusion, ginsan not only enhances immune responses but also avoids the pathologic inflammatory response to increase survival in MRSA-infected mice[81, 82]. It also induces a high humoral immune response against S. typhimurium with increasing serum IgG1, IgG2 and SIgA levels [8]. Western blot and RT-PCR confirmed that combined with an orally delivered antigen, ginsan specifically up-regulates the expression of COX-1, COX-2 and CCL3 mRNA in Peyer’s patches [8]. COX-1 and COX-2 are two inflammation mediators and can modulate MRSA inflammation[70]. They promote DC migration to the Peyer’s patch via CCL3, a chemo attractant for DCs [8]. Consequently, ginsan may serve as a potent vaccine supplement for oral immunization.
Ginsenoside, another ingredient of Pg, combats MRSA infection by stimulating immune responses and disrupting immune evasion. A Pg extract mainly consisting of ginsenoside can modulate the mRNA levels of TLR2/4, trigger the activation of the MyD88-dependent pathway and NF-κB signaling, and increase the mRNA levels of TNF-α and IL-1α, finally promoting monocytes-macrophage recruitment to combat the infection[83]. Ginsenosides isolated from Korean red ginseng can disrupt the structure of bacterial BFs and inhibit MRSA immune evasion [84]. The combination of ginsenosides and kanamycin/cefotaxime (conventional antibiotics) elicits synergistic or additive effects according to FICI indexes, which can be linked to altered cell membrane permeability [85]. When ginsenosides interact with MRSA-BF, the permeability of the plasma membrane to kanamycin could be increased [85]. Ginsenoside not only attenuates bacterial toxicity but also promotes the influx of antibiotics, which effectively inhibits immune evasion.
Ginseng oligopeptides (GOP), a dietary supplement derived from Pg, has immunomodulatory activities [86]. Oral administration of GOP can enhance the IIS and AIS, which may be due to increased macrophage phagocytosis and NK cell activity and the stimulation of Th cells (Th1 and Th2 cells) followed by antibody production (serum IgA, IgG1, IgG2b and intestinal SIgA) and cytokine secretion. Increased Th1 responses trigger IL-2 and IL-12 secretion, increased Th2 responses trigger IL-6 secretion and increased proportions of Tregs inhibit TNF-α [86].
4.1.3 Panax quinquefolius (aqueous extract of P. quinquefolius )
A patented aqueous extract from Panax quinquefolium (P. quinquefolius ), CVT-E002, is used to treat upper respiratory tract infection [87]. An in vivo study showed that it can improve the function of immune organs. It increases the NK cell numbers in mouse spleen and bone marrow [88, 89]. It also stimulates the proliferation of B-lymphocytes in the spleen of mice, and at doses of 10–500 Ag/mL, it increases IL-2 and IFN-γ levels in the spleen in a dose-dependent manner[87, 90]. In addition, it activates peritoneal exudate macrophages (PEM), leading to increases in NO, IL-1, IL-6 and TNF-α levels [90]. Additionally, it stimulatesin vivo IgG production in treated mice[90].
4.1.4 Ophiopogon japonicus (O. japonicus )
Ophiopogon japonicus (O. japonicus ) has various bioactivities, including anti-inflammatory and immunoregulatory activities. Its rhizome, as the primary medical portion, has been used to treat inflammatory diseases [91].
Ruscogenin (RUS) is a major effective steroidal sapogen in O. japonicus [92]. It exerts immunoregulatory activities mainly by inhibiting neutrophil infiltration and phagocytosis as well as blocking cell apoptosis, thus alleviating acute lung injury (ALI) and pneumonia caused by committee- or hospital-acquired MRSA (CA- or HA-MRSA) infection [93]. At doses of 0.3 kg/mL, 1.0 kg/mL and 3.0 kg/mL, RUS reduces neutrophil infiltration by decreasing MPO levels, thus inhibiting LPS-induced ALI in mice[94]. Additionally, it inhibits neutrophil phagocytosis [94]. This process might be associated with the suppression of NF-κB p65 phosphorylation and activation [94, 95]. Moreover, RUS inhibits the apoptosis of cells. Apoptosis is a common inflammatory characteristic of MRSA pneumonia and is critical for improving MRSA clearance as well as alleviating lung injuries [96, 97]. At a dose of 1 mg/kg, RUS inhibits LPS-induced apoptosis of pulmonary endothelial cells (PECs) by suppressing Bax and cleaved caspase-3 levels and by up-regulating Bcl-2 [96]. The high ratio of Bax/Bcl-2 is a well-recognized indicator of apoptosis. Bax accelerates apoptosis, and Bcl-2 inhibits apoptosis [98]. Cleaved caspase-3 is a pro-apoptosis marker [98]. The anti-apoptotic effects of RUS on PECs are accomplished by restraining NF-κB activation. This action occurring by inhibiting TLR4 and MyD88 expression, which then inhibits NO, IL-6 and TNF-α production[96]. TLR4 and its adapter protein MyD88 play an important role in the pulmonary inflammatory response[93]. MyD88 deletion can weaken the endocytosis of pathogens by neutrophils and decrease ROS and cytokines levels[99]. Taken together, RUS combats MRSA infection, especially MRSA-induced lung injuries by blocking neutrophil function and exerting anti-apoptosis effects.
Ophiopogon polysaccharide (OPS), another ingredient of O. japonicus, exhibits immune-enhancing activity in which macrophages are its main targets. It can induce the migration and recruitment of immune cells to infected sites by up-regulating IL-1β, TNF-α and other cytokines [100]. Additionally, it enhances the phagocytic function of macrophages by increasing iNOS and NO levels, ultimately enhancing the ability to kill pathogens[100]. Furthermore, OPS induces CD14 and MHC-II expression to promote macrophage activation and exert antigen-presenting functions, thus accelerating the initiation of the AIS[100]. Recently, immunological enhancement of OPS was markedly promoted by a drug delivery system via encapsulation with liposomes (OPS liposomes, OPSLs) [100].
4.1.5 Cordyceps sinensis and Cordyceps militarisC. sinensis , C. militaris
Cordyceps sinensis (C. sinensis ) and Cordyceps militaris (C. militaris ) are representative species ofCordyceps mushrooms [101, 102]. C. sinensis exerts anti-inflammatory and immunoregulatory properties[101]. It can attenuate LPS-induced pulmonary inflammation and fibrosis in vivo [101]. In LPS-induced ALI mice, C. sinensis extract (CSE) can improve pathological damage of lung tissue and reduce the degree of pulmonary edema in a dose-dependent manner. It reduces the number of neutrophils and macrophages, as well as MPO levels, thus alleviating inflammatory cell exudation, which is related to NF-κB signaling[101]. By inhibiting the phosphorylation of NF-κB p65 and downstream factors of NF-κB signaling (COX-2, iNOS), CSE down-regulates NO, TNF-α, IL-6 and IL-1β, thus inhibiting the inflammatory response [101].
C. militaris is another representative species of this genus and shows immunomodulatory effects [102]. Cordycepin (Cor) is the representative component [102]. Cor regulates the secretion of inflammatory mediators and pro-inflammatory cytokines by affecting the TLR4/NF-κB pathway in macrophages[103]. It can inhibit neutrophil exudation and phagocytosis by decreasing MPO levels and down-regulating iNOS/NO expression and improve lung edema and inflammatory responses by regulating inflammatory cytokines, including TNF-α, IL-6, HMGB1 and IL-10. This regulation occurs through the up-regulation of heme oxygenase-1 (HO-1) in a dose-dependent manner [104, 105]. HO-1, an antioxidative enzyme, can reduce free hemoglobin with pro-inflammatory activity in vivo , and produce by-products possessing anti-inflammatory activities [106]. Cor can increase the mRNA and protein levels and enzymatic activity of HO-1 in a dose-dependent manner, inhibiting inflammatory responses[105]. HO-1 can further attenuate inflammation and injuries in the lung through down-regulating TNF-α, IL-6 and HMGB1 and up-regulating IL-10 [105]. IL-10 can inhibit inflammation [104]. HO-1 and IL-10 promote each other’s expression and cooperate to inhibit inflammation. HMGB1, an inflammatory cytokine, is recognized by TLR4 and induces inflammation, which is promoted by nucleocytoplasmic translocation of HMGB1[107]. In conclusion, Cor exerts a protective effect by increasing Nrf2/HO-1 signaling and decreasing NF-κB signaling[104, 105]. Nrf2 is an upstream regulator of HO-1. The expression of Nrf2 in the cytoplasm and nucleus before and after Cor intervention shows that Nrf2 activation and transformation from the cytoplasmic into the nucleus are the mechanisms for the induction of HO-1 expression [104, 105].
4.1.6 Atractylodes species Atractylodis Rhizoma (Atractylodes macrocephala polysaccharide)
Atractylodes species are composed of two major groups,Atractylodes lancea (Thunb.) DC. (A. lancea ) andAtractylodes macrocephala Koidz. (A. macrocephala ). Extracts from Atractylodes species including lactones and polysaccharides, exert anti-inflammatory, antibacterial and immunomodulatory activity and improve gastrointestinal function[108]. A. macrocephala extract at 1.562 mg/mL, 3.125 mg/mL and 6.25 mg/mL concentrations can inhibit MRSA in a dose-dependent manner [109]. Atractylenolide I (AO-I), a major bioactive component isolated from A. macrocephala , has anti-inflammatory effects[110]. It exerts a protective effect on LPS-induced ALI mice by inhibiting the phagocytic activity of neutrophils and macrophages [110]. By inhibiting TLR4, NF-κB activation and IκB-α degradation, it decreases MPO levels, thus suppressing the numbers and phagocytic activities of neutrophils and macrophages in the BALF. Finally, AO-I exerts anti-inflammatory activity by inhibiting TNF-α, IL-1β, IL-6, IL-13 and macrophage migration inhibitory factor (MIF) [110]. IL-13, a Th2 cytokine, induces airway inflammation [111]. MIF is released by bacterial antigen-stimulated macrophages, promoting infiltration and phagocytosis of macrophages in response to airway inflammation [112]. Notably, MIF shows greater deleterious effects in chronic inflammation than in acute one[113]. Hence, it is necessary for anti-inflammatory agents to inhibit these cytokines. Additionally, AO-I can directly up-regulate IL-10 to promote inflammation resolution[110]. It also inhibits antibiotic-induced dysbiosis of the intestinal microbiome [114]. Hence, it may be a promising method to combine A. macrocephalawith antibiotics for MRSA infection, because it not only enhances the ability to resist pathogens but also reduces the disruption to the normal intestinal flora by antibiotics. A. macrocephalapolysaccharides (AMPS), another component in A. macrocephala , exert immunoregulatiory activity. In contrast to AO-I, AMPS induces IκB degradation, activates NF-κB and then up-regulates NO and TNF-α, thus improving the phagocytic activities of macrophages and enhancing the IIS in a dose-dependent manner [115, 116].
In A. lancea , an acidic polysaccharide (ALP-3) is a component deserving attention. It can modulate macrophage functions, including promoting macrophage proliferation and phagocytosis, and releasing NO, TNF-α and IL-6. In addition, it exerts intestinal immune activities[117]. It can directly stimulate myeloid cell proliferation in Peyer’s patch cells and induce them to enhance the production of hematopoietic growth factors (HGF). HGF acts on the impaired intestinal mucosa and promotes intestinal mucosal repair[117]. Briefly, A. lancea and A. macrocephala provide a protective effect on MRSA infection, especially on pulmonary injuries mainly by inhibiting inflammation and improving MIS.
4.2 Formulae
4.2.1 Zhenqi Capsule
Zhenqi capsule (ZQ) is composed of Astragalus membranaceus(A. membranaceu ) and Ligustrum lucidum . It is commonly used to improve immunity, increase leukocyte numbers, and promote the recovery of normal functions after surgical operation, radiotherapy, or chemotherapy [118]. An analysis of the tissue distribution of the main bioactive components of ZQ suggests that these components show overall high levels in the spleen and thymus, suggesting that these components mainly accumulate in organs associated with the immune response, confirming their immune effect[118]. Of these components, astragaloside IV with its higher tissue concentration and bioavailability in vivo , has become an index of quality control of ZQ [118]. The extract from Ligustrum lucidum contains potent immune stimulants and influences immune restoration[119].
Astragali Radix (AR) is one of the major tonics in TM. AR polysaccharide (ARPS), the representative component of AR, has effects on immune regulation and inflammation [120]. In anAeromonas hydrophila -infected mouse model, ARPS balances the inflammatory status in infected sites. It enhances the phagocytic activities of phagocytes by stimulating macrophage and NK cell activity. It also inhibits neutrophil phagocytic activity and reduces MPO levels, preventing potential poor prognosis due to excessive neutrophil infiltration [68]. Additionally, its immunostimulatory activity is involved in activating T-helper cells and stimulating cell division and transformation in lymphocytes[68]. It lowers the proportion of CD8+ T cells and increases the ratio of CD4+/CD8+ T cells, representing an increase in immunity [68]. ARPS induces the activation of CD4+ T cells in mice with P. aeruginosa infection[121].
4.2.2 Yupingfeng San
Yupingfeng San (YPFS) is composed of AR, A. macrocephala andSaposhnikoviae Radix (SR). Clinically, YPFS has beneficial immune-modulatory effects and has been used to prevent and treat bacterial infection as well as upper respiratory tract infection[122]. Based on its network pharmacology analysis, it is associated with the bacterial invasion of epithelial cells and other bacterial infections, which is consistent with its clinical uses[123]. It is also linked with aminoacyl-tRNA biosynthesis, which is a representative pathway to reflect the inhibitory effect of an herbal formula in combination with antibiotics on MRSA-BF infection [12, 123]. Furthermore, it is involved in the NF-κB signaling pathway, chemokine signaling pathway, leukocyte trans-endothelial migration, endocytosis and antigen processing and presentation [123, 124].
The bidirectional regulatory effect on the expression of inflammatory factors is one of the features of this formula. It helps the immune system achieve a balance between the expression of pro-inflammatory and anti-inflammatory cytokines in the process of combating MRSA infection. In acute inflammation models (LPS-induced for 3 hours), YPFS activates NF-κB by enhancing the degradation of IκB-α, inducing the mRNA and protein expression of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in a dose-dependent manner, with maximal induction reaching approximately 2- to 20- fold of the original[124]. However, when in chronic inflammation models (for 24 hours), it suppresses these cytokines, exerting anti-inflammatory effects [124]. In this process, it is key events to bidirectionally regulate these inflammation mediators (iNOS, COX-2) [125]. It depresses iNOS and COX-2 levels in macrophages at the 3-hour time point; however, at the 24-hour time point, it exerts the opposite[125]. The iNOS, an enzyme in macrophages, assists macrophages in combating pathogens. However, when MRSA-BF is formed after 24 hours, it helps MRSA evade attack by the immune system, which promotes macrophages toward anti-inflammatory or profibrotic M2 phenotype polarization [42, 126]. One of the features of a typical M2 macrophage response is decreased iNOS levels, which promotes profibrotic responses and abscess production during chronic MRSA infection [42, 127]. Similarly, COX-2 is an inducible enzyme, and its expression is up-regulated in the initial stages of inflammation and tissue injury such as MRSA-induced acute skin injury. If this high expression continuously occurs, it can lead to severe damage to the body [70]. Therefore, moderate expression of iNOS and COX-2 plays a protective role against MRSA infection. Overall, YPFS balances complex immune responses against MRSA infection by exerting bidirectional modulating functions, which is hardly found in conventional drugs [128].
In addition, AR, A. macrocephala and SR have bidirectional regulatory effects on cytokines, including COX-2 and iNOS[124, 129]. The glycoprotein derived from A. macrocephala stimulates TNF-α production in splenocytes, yet other components of A. macrocephala , AO-I and III, exert anti-inflammatory activities by suppressing TNF-α production[130, 131]. SR water extracts can up-regulate iNOS. However, the other three SR-derived active ingredients inhibit iNOS expression [125, 132]. Thus, a single herb may exhibit a greater immune stimulation effect than YPFS. Bidirectional regulation is a unique advantage of herbal formulae. Apart from enhancing the IIS, YPF-PS derived from YPFS enhances T lymphocyte proliferation. It promotes lymphocyte entry into S and G2/M phases, and thus effectively increases the percentages of CD4+ and CD8+ T cells, greatly potentiating the cell immune responses[133].
4.2.3 Shengmai San
Shengmai San (SMS) is composed of Pg, O. japonicas andSchisandra chinensis (S. chinensis )[134]. It is a classic tonic prescription for chronic pulmonary diseases, such as syndromes of weakness and shortness of breath, with powder and injection commonly used clinically[135, 136]. SMS combats MRSA infection by regulating immunity and inflammation. It is highly recommended for use in combination with antibiotics for CA-MRSA in clinical guidelines, with an effective rate up to more than 80% [137]. A meta-analysis showed that when treating chronic obstructive pulmonary disease (COPD), SMS combined with Western medicine has greater efficacy than Western medicine alone, which provides a partial basis for SMS combined with conventional therapies in the treatment of MRSA infection[138]. It can also combat sepsis by protecting the MIS of mice [139]. At a dose of 1.5 mL/kg, SMS regulates NF-κB and decreases IFN-γ, TNF-α and IL-2 levels, thus inhibiting excessive inflammation and exerting its anti-septic activity[139]. Metabolomics analysis suggests that the key mechanism of this activity is embodied in SMS regulating taurine and taurine metabolism, as well as arginine and proline metabolism[139]. These metabolic processes have also been regulated in Reyanning combined with linezolid against MRSA-BF infection[12, 140]. These effects of SMS are echoed by network pharmacology analysis in which SMS can regulate the processes of immunity and inflammation [141].
S. chinensis is one of the herbs in this formula. Schisantherin A (SA), isolated from the fruit of S. chinensis , shows a protective effect on acute inflammatory lung injuries by improving the IIS[142]. It inhibits neutrophil and macrophage activities and reduces neutrophil infiltration[143]. Besides, it inhibits NF-κB signaling and MAPKs signaling, and then it decreases TNF-α, IL-6 and IL-1β levels in the BALF, thus exerting anti-inflammatory effects and improving pulmonary injuries [143].
4.2.4 Buzhongyiqi Tang (Hochu-ekki-to, TJ-41)
Buzhongyiqi Tang, known as Hochuekkito (HET), TJ-41, is a formula in both traditional Chinese medicine and Japanese Kampo medicine. This formula comprises 10 herbs, including AR, Pg, A. lancea ,Angelicae radix , Zizyphi fructus , Aurantii nobilis pericarpium , Bupleuri radix , G. glavra , Cimicifugae rhizome and Zingiberis rhizome [144]. HET has anti-infection and anti-inflammatory effects and exerts trophic support functions [145]. It not only directly reduces or prevents MRSA colonization, but also combats MRSA infection by regulating the MIS. In a small-scale clinical trial for MRSA carriers’ patients, HET eradicated MRSA successfully with no side effects [144]. It also prevents MRSA colonization by improving serum nutrition levels and enhancing the IIS[144, 145]. HET also up-regulates the activity of splenocytes, which is the major immunomodulation system of anti-bacterial infection [144].Atractylodes rhizome, Zingiberis rhizoma andBupleuri radix promote the immunostimulation of spleen cells.Atractylodes rhizome extract promotes T-cell activity by expressing CD28 in T cells in the spleen [144].Zingiberis rhizoma extract stimulates CD8+ T cells of splenocytes[144]. Bupleuri radix extract has antimicrobial activity [146]. In addition, it also promotes B-cell mitogenic activity in spleen cells[144]. Thus, for MRSA carriers who are not recommended to use conventional drugs, HET seems to be a more effective option. Additionally, HET decreases vulnerability to MRSA infection[147].
Furthermore, HET exerts immunomodulation by regulating the MIS in the upper respiratory or intestinal tract to resist bacterial infection. Specifically, oral administration of HET can increase IgA levels in intestinal, which is the key indicator to evaluate mucosal antibody responses [148]. It can directly enhance mucosal IgA antibodies by modulating cytokine secretion by intestinal epithelial cells (IECs). Additionally, it is inferred that HET could increase SIgA secretion and enhance immune responses [9, 148]. DNA microarray and flow cytometry analyses show that oral administration of HET increases the proportion of L-selectin-positive cells in B lymphocytes in Peyer’s patch cells and peripheral blood mononuclear cells [148]. L-selectin promotes the recruitment of B-lymphocytes to the non-intestinal mucosal effector site, which partly explains the reason for the enhancement of the IgA immune response in the nasal mucosa [148]. In summary, HET exerts anti-MRSA efficacy by regulating immune organs and the MIS.

Table 2. The effect of TM therapies on host immunity and MRSA immune evasion.