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 militaris (C.
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.