Novel coronavirus pneumonia (COVID-19) remains a potentially life-threatening global pandemic acute infectious disease characterized by inflammatory storms, coagulation disorders, and organ damage (34). MDSCs with immunomodulatory activity were found to play an important role in mediating the excessive inflammation or inflammatory storm of COVID-19, and MDSCs can limit infection-induced excessive inflammation or inflammatory storm and protect host immunity (34); on the other hand, excessive inflammation or inflammatory storms also lead to accumulation of MDSCs in the peripheral blood of COVID-19 patients, participate in the pathological process of the disease, and correlate with the severity of the disease (8, 35–39). Significantly, a link between MDSCs and COVID-19 has been identified in a number of recent investigations ( Table 1 ). Compared with healthy subjects or patients with mild COVID-19, the frequency of PMN-MDSCs in the peripheral blood of COVID-19 increases with disease exacerbation, especially in severe instances and deceased patients, and proliferating PMN-MDSCs will further suppress T cells, resulting in a reduction in lymphocytes and further compromising the host immune response, so establishing a vicious cycle (7, 20, 44, 45). Comparison with indicators reflecting disease severity (levels of C-reactive protein, ferritin, and lactate dehydrogenase) demonstrated that these indicators were elevated with PMN-MDSCs in severe cases, especially immature PMN-MDSCs, confirming a positive correlation between PMN-MDSCs and COVID-19 severity (41). A 1% increase in PMN-MDSC frequency was independently related with a 3% increase in the probability of fatal outcomes, as determined by an age- and gender-adjusted Cox regression model (20). In contrast to these results, Japanese researchers found that the frequency of PMN-MDSCs (but not other MDSC subgroups) may be transiently elevated in patients surviving severe COVID-19 compared to patients dying from severe COVID-19, and the investigators suggest that PMN-MDSCs may reduce detrimental immune responses and be associated with genetic factors (36). In severely sick individuals, low levels of PMN-MDSCs may aid in survival (45). However, the majority of investigations have revealed that the frequency of M-MDSCs in peripheral blood following COVID-19 therapy is substantially linked with disease severity (8, 37). Analysis of SARS-CoV-2 viral RNA burden revealed a connection between M-MDSCs and viral load, indicating that SARS-CoV-2 infection may inhibit host immunological responses by encouraging the proliferation of M-MDSCs (43). M-MDSCs inhabit CD4+ and CD8+ T cell proliferation and IFN-γ production through an Arg-1-dependent mechanism, with downregulation of CD3ζ chain expression (8). Despite the fact that MDSCs and cytokine levels (such as IL-6, TNF, IL-1, etc.) remained persistently elevated during the recovery phase of COVID-19, this also suggests that MDSCs exerted an inhibitory T-cell recall response, that the suppressive activity of T cells persisted after recovery from infection (39, 42). It can be seen that M-MDSCs not only suppress the immune activity of T cells during the acute episode after SARS-CoV-2 infection, but also have a recall response to suppress T cells during the recovery period. In conclusion, the results of different studies may vary, but MDSCs exhibit different phenotypic characteristics and functional status with various stages of COVID-19, and MDSCs, as one of the key pathogenic factors of COVID-19 inflammation and immunosuppression, may be a major target for treatment (30, 46, 47).

Inflammatory cytokines are one of the primary mechanisms that induce expansion of MDSCs and are the focus of research on COVID-19-targeted therapy (40, 48). The pro-inflammatory cytokine IL-6 phosphorylates STAT3 via the gp130/JAK/STAT pathway, hence regulating M-MDSC differentiation, proliferation and survival in human and animal disease conditions including COVID-19 (49–51). In addition, studies have shown that IL-6 levels rise with the degree of illness in individuals with severe disease (7, 8, 52). Therapeutic modulation of IL-6 levels by anti-IL-6 receptor antagonists (tocilizumab, sarilumab) reduces the duration of COVID-19 and/or reduces the severity of the disease (53–55). In vitro culture of PBMC isolated from peripheral blood of COVID-19 patients revealed that 5-fluorouracil (5-FU) restored lymphocyte proliferation and propagated Th1-mediated immune response by decreasing levels of MDSCs and decreasing production of IL-10, IL-8, IL-17, and Th2 cytokines, while boosting production of IFN-γ and IL2 (38). In COVID-19 therapy, it has been proposed that 5-FU in conjunction with deoxyribonucleosides and deoxyribose may have antiviral effects (56). In addition, it has also been hypothesized that vitamin D deficiency increases the risk of developing ARDS in COVID-19 patients and that vitamin D supplementation may attenuate the inflammatory response caused by pulmonary macrophages and MDSCs in COVID-19 patients and reduce acute respiratory distress syndrome in COVID-19 patients (57). Despite the fact that the aforementioned studies demonstrated that targeting MDSCs for the treatment of COVID-19 may be more effective, these studies are still restricted to in vitro cell culture and clinical trials, and the particular therapeutic processes need more research.

Tuberculosis is a devastating infectious disease caused by Mycobacterium tuberculosis, as of the year 2020, it has superseded SARS-CoV-2 as the second most infectious disease killer, with roughly 1.3 million fatalities every year (58). Although BCG vaccination and antituberculosis chemotherapy have been extensively utilized for TB prevention and treatment, the consequences have been unsatisfactory (6, 59), thus, it has become necessary to investigate alternative antituberculosis treatment strategies. MDSCs have been found to make a significant contribution in the pathology of TB, and the majority of studies indicate that MDSCs provide ecological niches for the survival of Mycobacterium avium in the lungs of infected hosts and promote replication of Mycobacterium tuberculosis at the site of pulmonary infection (5, 6, 60, 61). Recent investigation has shown that Mycobacterium tuberculosis may employ the MPT64 protein to stimulate the creation of MDSCs, hence facilitating its survival and evasion of host immunological defenses (62). MDSCs not only accumulate in the peripheral blood of M. tuberculosis model mice (63), but also in the spleen of M. tuberculosis-infected mice (64). In addition, an increased frequency of MDSCs was observed in peripheral blood, bronchoalveolar lavage fluid, and pleural fluid specimens from patients with pulmonary or extrapulmonary tuberculosis, and the frequency of circulating MDSCs also decreased significantly at the end of antituberculosis treatment, indicating that MDSCs play an important role in the pathogenesis of tuberculosis (6, 65–69). In vitro granuloma model tests have shown that human MDSCs activate MAPK channels, hence boosting IL-1O production and Mycobacterium tuberculosis replication (60). The results of studies on TB patients also confirm the correlation between MDSCs and disease ( Table 2 ). The frequency of both subpopulations of MDSCs was elevated in PBMC of patients with active TB, was dominated by M-MDSCs, reduced the immunological function of lymphocytes in TB patients, and was proportional to the severity of the disease (67–70). Other investigations have shown that the levels of PMN-MDSCs are elevated in the peripheral blood and bronchoalveolar lavage fluid of patients with active TB, and that these levels correlate with plasma nitric oxide levels (6, 72). Grassi et al. established the link between PMN-MDSCs and TB severity by confirming by chest X-ray and experiment that PMN-MDSCs levels were higher in patients with milder disease severity than in those with more severe disease severity (71). Bindu et al. further found through studies on non-human primate TB granulomas that PMN-MDSCs levels were elevated in animal models of active TB (ATB) compared to latent TB-infected animals and were located in the lymphocyte cuffs surrounding the granuloma, thereby inhibiting T-cell entry into granuloma’s core (73). These results indicate that MDSCs may represent a novel target for TB host-directed treatment and a possible signal for detecting success.

Host-directed therapy (HDT) is a novel approach to innovative host-specific therapies designed to reduce excessive inflammation or enhancing the host’s immune defense against pathogens, with the goal of shortening treatment regimens without inducing drug resistance (74). Several FDA-approved medicines, including all-trans retinoic acid (ATRA), cyclooxygenase-2 inhibitor (COX-2i), phosphodiesterase-5 inhibitor (PDE-5i), and sildenafil, have been validated in the treatment of tuberculosis (TB) (61, 69, 74–76). It was found that MDSCs levels were excessively elevated in the lungs of a mouse model of tuberculosis, which was related with increased mortality, and the frequency of MDSCs decreased while the number of T cells rose after host-directed therapy with all-formic retinoic acid (ARTA) (61). COX-2i has been demonstrated to reduce pathological lung damage caused by the host immunological response in tuberculosis patients (76). Combining COX-2i with anti-inflammatory effects with anti-tuberculosis basal treatment reduced cytokines that induce high levels of M-MDSCs, including IL-1, IL-10, IL-6, TNF, and S100A9 (69). Combining PDE-5i sildenafil with antituberculosis basal therapy improved treatment efficacy because PDE-5i sildenafil increased cyclic adenosine monophosphate (cGMP) in MDSCs, leading to a decrease in Arg-1 and nitric oxide synthase 2 (NOS2), thereby decreasing the mechanism of MDSCs-induced T-cell suppression (74). However, Vinzeigh N et al. demonstrated that sildenafil was incapable of reversing MDSCs-mediated T-cell suppression and had little effect on enhancing host immunity (77). The above findings for MDSCs-targeted therapy suggest that MDSCs may be a new target for anti-tuberculosis host-directed therapy, but the results are contradictory and additional investigation is required.

Studies on the correlation between MDSCs and infectious lung diseases have included lung injury caused by pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Pneumocystis carinii, in addition to the two specific pathogens mentioned above. In a mouse model of Streptococcus pneumoniae pneumonia, MDSCs levels are elevated in model mice’s circulation and are associated with a choline-binding protein, although the specific mechanism remains unclear (78). However, the results of an animal experiment combined with clinical trials suggest that the macrolide antibiotic clarithromycin promotes elevated levels of MDSCs in the circulation of animals and humans through a particular mechanism that promotes the expansion of MDSCs (CD11b+Gr-1+) through the STAT3/Bv8 axis, decreases INF-γ, boosts IL-10 levels, and protects the organism from post-influenza Streptococcus pneumoniae infection (79). Staphylococcal enterotoxin B secreted by Staphylococcus aureus induces an increase in circulating levels of MDSCs in Staphylococcus aureus-infected mice, and treatment with resveratrol increases the proportion of circulating MDSCs because MDSCs can downregulate the body’s immune response to prevent tissue damage at the site of inflammation (80). MDSCs play a pivotal part in the efferocytosis of neutrophils following infection with Klebsiella pneumoniae, and elevated levels of MDSCs in animal models of Klebsiella pneumoniae pneumonia promote IL-10 production in the late stages of infection to facilitate the efferocytosis of apoptotic neutrophils and reduce lung injury (10, 81). It has also been hypothesized that the early expansion of M-MDSCs during an infection terminates the proinflammatory signaling essential for the clearance of Klebsiella pneumoniae, hence causing a chronic infection (82). While the particular mechanism of MDSCs in Klebsiella pneumoniae pneumonia remains a complicated process, it is known that MDSCs are involved (83). Both in clinical trials and in animal studies, P. aeruginosa infection leads to increased levels of circulating PMN-MDSCs in patients with chronic inflammatory diseases of the lung, including pulmonary cystic fibrosis, disrupting the host immune response (84). Levels of MDSCs in alveolar lavage fluid in animal models of Pneumocystis pneumonia (PcP) increase with increasing numbers of Pneumocystis carinii in the organism and with increasing lung inflammation; moreover, secondary transfer of MDSCs may directly cause lung damage in normal mice (85). Treatment with immunosuppressive drugs and antibiotics (all-trans retinoic acid combined with Primaquine) transforms MDSCs in the lung into alveolar macrophages capable of clearing Pneumocystis infection, enabling the host to successfully fight against infection (86). Further studies revealed that MDSCs are depleted of alveolar macrophage phagocytic activity during PcP via the PD-1/PD-L1 pathway (87). Despite the fact that the majority of the aforementioned studies on other pulmonary infectious diseases are limited to animal experiments, the fact that MDSCs are associated with the disease, for better or for worse, regardless of the type of pulmonary infectious disease may indicate that MDSCs are poised to become another therapeutic target for these diseases.