The CVM plays a significant role in shaping the immune response responsible for HPV clearance [
8]. The bacterial or viral components are recognized by epithelial cells through TLRs, activating the innate immune response by releasing various pro-inflammatory cytokines [
87,
128]. Macrophages and dendritic cells (DCs), as antigen presenting cells (APCs), are then activated and recruit immune effector cells, such as Natural Killer (NK) cells. APCs also stimulate antigen-specific T cells and B cells to activate the adaptive immune response.
CVM dysbiosis is associated with increased pro-inflammatory cytokines that can stimulate cell proliferation and promote the development of cervical cancer [
108,
109]. Studies have shown that CST IV is related to the increase of IL-1α, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-10 in cervix and vagina [
130]. CST III is associated with increased IP-10 and monokine induced by interferon-γ (MIG) compared with CST I/II [
130].
When it comes to specific cervicovaginal microbial species,
Lactobacillus usually plays a protective role in vaginal immunomodulation.
Lactobacillus has the capacity to improve antiviral defenses and modulate inflammation-mediated damage [
108]. Lacobacilli can promote the epithelial cells to release surfactant proteins [
57]. For example,
L. gasseri LGV03 can significantly increase the production of interferon α (IFN-α) and IFN-β in HPV-positive cervical epithelial cells and reduce the expression of the pro-inflammatory cytokines like IL-6, IL-8, and IL-1β [
71]. Lactic acid produced by
Lactobacillus can act directly on the cervicovaginal epithelium, inducing the production of the anti-inflammatory cytokine, such as IL-1Ra, and reducing pro-inflammatory cytokine production [
131]. In comparison,
G. vaginalis or
Prevotella bivia usually induce the increase of pro-inflammatory cytokines, like IL-6, TNF-α, IL-1α, and MMP-9 [
108].
Fannyhessea vaginae and
Sneathia amnii elicit more robust cytokine responses, including IL-6, IL-8, IP-10, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 3α (MIP-3α), RANTES, MMP-10, and MMP-1 [
108]. Other BVABs, such as
Eggerthella, only causes an increase in IL-1α;
Mobiluncus mulieris increases IL-1α, IL-6, IL-8, MCP-1, and TNF-α; while
Megasphaera micronuciformis increases IL-1α, IL-1β, IL-1RA, TNF-α, and IL-6 [
132].
These altered cytokines can serve as immune markers to predict BV status, HPV clearance, and CIN progression. It’s reported that high IL-1β/IP-10 ratio in BV is associated with lower rate of hrHPV clearance [
110]. Elevated TNF-α/MIP-1β ratio in BV is prospectively associated with progression of persist HPV infections to CIN [
110].
BVABs also stimulate the maturation and differentiation of APCs.
Megasphaera elsdenii and
Prevotella timonensis significantly promote the maturation of DCs, while the effects of
G. vaginalis and
Lactobacillus are not obvious [
133].
G. vaginalis and its supernatants can induce THP-1 macrophages to differentiate into the M1 phenotype, which is involved in defence against bacterial infections, elevated ROS levels, and stimulation of the NF-κB/STAT1 (Signal Transducer and Activator of Transcription 1) pathway [
134]. In contrast, vaginal
Lactobacillus promotes M2 macrophages polarisation, which is involved in tissue repair and wound healing, helpful to restore the integrity of epithelial barrier [
135].