The microbiome and viriome are subtle but important components of the tissue microenvironment that influence tissue homeostasis. Until recently, it was believed that “respiratory infections” very rarely cause complications and should not be taken into account when predicting possible recurrences of a persistent infection, such as a viral one.

At the same time, an increasing number of observations indicates a significant impact of transferred COVID-19 on the state of the microbial environment. It has been shown that SARS-CoV-2 infection can lead to reactivation of oncogenic viruses in tissues. For example, a severe form of COVID-19 causes reactivation of cytomegalovirus (CMV) and the herpes simplex virus (HSV) ^[1][6] (Table 1).

Microbiome	Changes by COVID-19
Cytomegalovirus (CMV) and Herpes simplex virus (HSV)	Are reactivated [1][6]
Firmicutes	Significant decrease in microbiome [2][7]
Bacteroidota	Increase [2][3][4][7,8,9],
Lactobacillus	Decrease [2][7], decrease after menopause [3][8]
L. crispatus, L. iners, L. gasseri, and L. jensenii	Relative abundance was lower [2][7]
Ureaplasma	The amount was higher in women with moderate/severe than with asymptomatic/mild disease [2][7]; increase [3][8]

At the same time, in an in vitro study on cell lines (human umbilical vein endothelial cells (HUVEnCs), human colorectal adenocarcinoma cells (Caco-2), and retinal pigment epithelial cells (RPE-1s)) using blood serum from patients with a history of previous human cytomegalovirus (HCMV) infection significantly increases the possibility of SARS-CoV-2 entry into cells by activation of ACE2, the SARS-CoV-2 cell entry receptor ^[5][10]. COVID-19 also induces some human endogenous retroviral elements (HERVs), replication- and retrotransposition-defective sequences of ancient viral origin integrated into the human genome millions of years ago. It has been described that SARS-CoV-2 induces expression of the envelope protein of the human endogenous retrovirus type W in blood lymphocytes and tissues of patients with COVID-19 ^[6][11]. HERVs are known to promote development of cancer features, including genome instability ^[7][12]. Increases in the levels of some HERVs is a molecular characteristic of endometrial carcinoma (EC); for example, the HERV-W envelope gene syncytin-1 (which, in particular, is required for human placental morphogenesis due to its regulatory role in formation of syncytia) is significantly increased in EC ^[8][13]. Notably, cell fusion involving cancer cells and mediated by HERVs plays an important role in cancer initiation and progression ^[9][14]. Although the causal roles of the herpes simplex virus (HSV) and cytomegalovirus (CMV) in EC are unclear, it has been suggested that they may be involved in the pathogenesis of EC ^[10][11][15,16]. A role for HERVs in pulmonary fibrosis has also been hypothesized ^[12][17]. However, given the novelty of SARS-CoV-2 infection, nothing is known about the interaction of EC, UF, and COVID-19 in such a context. Thus, it may be of interest to evaluate whether COVID-19 affects HERVs and oncogenic viruses in EC and UF and whether they can be used as prognostic or therapeutic biomarkers in the clinic. COVID-19 may also lead to alteration of the FRS microbiome ^[2][7]. For example, it changes the composition of the vaginal microbiome, causing dysbacteriosis with significant reductions in some taxa and increases in others: in particular, an increase in bacteria of the Bacteroidota type (p = 0.018) and a decrease in the genus Lactobacillus (p = 0.007). When subgroups were analyzed, the number of Ureaplasma spp. was higher in women with moderate/severe disease than in women with asymptomatic/mild disease ^[3][8]. Although the uterus is a low-microbial site, it is not free from bacteria ^[13][18]. The endometrial microbiome has been fully characterized, and pathological conditions such as EC have been demonstrated to be associated with significant changes in microbiota ^[14][19]. It is to be expected that changes in the normal microbiome lead to chronic inflammation, which can also cause fibrotic changes as well as open up new relationships with development of FRS pathologies ^[15][20].

2. The Impact of COVID on Comorbidities and the Background State of the Body

As is known, COVID-19 is a systemic disease, or, according to ^[16][21], “COVID-19 is a multi-organ aggressor”. Case reports have shown multiple systemic effects of COVID-19 infection, including acute respiratory distress syndrome, fibrosis, colitis, thyroiditis, demyelinating syndromes, and mania, indicating that COVID-19 can affect most human body systems ^[17][18][22,23]. The most susceptible to the severe course of the disease are the elderly and people with concomitant diseases. It is known that SARS-CoV-2 affects men more strongly, which is associated with the level of hormones that affect expression of the ACE2 receptor ^[19][24]. It has been demonstrated that ACE2 levels are reduced in patients with diabetes mellitus, and at the same time, a history of diabetes is a risk factor for COVID-19 ^[20][25]. Some of these risk factors, such as older age, obesity, and sex hormone levels, are among the risk factors not only for COVID-19 but also for EC and UF ^[21][22][23][26,27,28]. However, there is a surprising reduction in the risk of UF among people with diabetes, whereas having a history of diabetes is a risk factor for COVID-19 and EC ^[24][29]. Development of diabetes mellitus, maternal adiposity, and insulin-dependent gestational diabetes are associated with COVID-19 in pregnancy ^[25][30]. A case of hypothalamic amenorrhea after SARS-CoV-2 infection in a 36-year-old healthy woman has been described ^[26][31]. As in the olfactory epithelium, high levels of ACE2 and TMPRSS2 are found in the ovaries and endometrium ^[27][32] and the luminal and glandular epithelial cells of the FRS ^[28][33]. It is also known that ACE2 levels in the endometrium fluctuate depending on the phase of the menstrual cycle ^[29][34]. ACE2 is widely expressed in human myometria and uterine leiomyoma ^[30][35]. Another study showed that ACE2 and TMPRSS2 are also expressed in EC cells ^[31][36]. Finally, ACE2 levels have been shown to be elevated in EC compared to in adjacent noncancerous tissue ^[32][37]. This gives reason to pay close attention to the development of possible pathological processes in the female system when it is infected with the SARS-CoV-2 virus. A large body of research addresses the practical issue of the persistence of the SARS-CoV-2 virus in the FRS. Prospective studies indicate both the presence ^[33][38] and absence of the virus in the lower genital tract ^[34][39]. Such interest is primarily due to assessment of the impact of the virus on the course of pregnancy and the safety of IVF procedures. A multicenter study of 906 couples undergoing IVF showed that resulting COVID-19 infection prior to egg retrieval had no clear negative impact on egg and embryo outcomes, including the number of eggs retrieved, the rate of egg maturation, the normal fertilization rate, or the number of good-quality embryos. However, the results of linear regression in that study showed that the utilization rate of eggs retrieved after 7 days after infection was higher ^[35][40]. In addition, the subsequent identification of alternative pathways for the virus to enter, as well as symptoms associated with development of inflammation, cytokine storms, and microvascular damage, means that parallel pathogenetic processes occur in the body during infection with COVID-19. Thus, endothelial dysfunction of the vasculature due to COVID-19 is observed throughout the body ^[36][41] and can subsequently affect multiple organs, including FRS organs, regardless of the levels of ACE2 in the cells that make up the affected organ. In addition, in studying the placenta, in some cases (especially after preterm birth), complications were found in the form of diffuse and localized SARS-CoV-2 placentitis (infection of the placenta) ^[37][42]. All placentas showing the three classic features, diffuse villous agglutination, placental syncytiotrophoblast (ScT) necrosis, and histiocyte-dominated inflammatory infiltrate with varying amounts of perivillous fibrin, were found to be positive for SARS-CoV-2 with immunohistochemistry (IHC). Overall, we agree with the view presented by Saadedin et al. that although ACE2 is expressed in FRS tissues, its role is not predominant in the adverse effects of COVID-19 on the FRS ^[17][22]. However, given the complex system of tissue regulation of the FRS and the potential for asymptomatic and incidental detection of endometrial cancer, such as in spontaneous abortion ^[38][43], more information needs to be collected about negative effects as well as the positive ones. As an example, a case of spontaneous tumor regression after vaccination against COVID-19 was described ^[39][44].

3. Impact of COVID-19 on the Extracellular Matrix

SARS-CoV-2 induces several growth factors associated with tissue fibrosis. In patients with moderate severity of COVID-19, TGF-α, FGF-basic, and EGF levels were shown to be significantly elevated but decreased with progression of severity ^[40][88]. An increase in the level of TGF-β under the influence of SARS-CoV-2, which led to remodeling of the vascular extracellular matrix, was also shown ^[41][89]. In studying the placenta, in a number of cases (especially after preterm birth), complications in the form of diffuse and localized SARS-CoV-2 placentitis (infection of the placenta) were found in patients with COVID-19. All placentas showing the three classic features of placentitis, diffuse villous agglutination, placental syncytiotrophoblast (ScT) necrosis, and histiocyte-dominated inflammatory infiltration with varying amounts of perivillous fibrin, were found to be positive for SARS-CoV-2 with immunohistochemistry (IHC) ^[37][42]. The outcomes of such inflammation are also tissue fibrosis and remodeling of the extracellular matrix. COVID-19, through metabolic changes, also affects the so-called advanced-glycation end products/receptor for the advanced-glycation end-products (AGE/RAGE) axis in the host ^[42][90]. RAGE is a well-known driver of inflammation and contributes to the “oncogenic” niche. The ECM is the cornerstone of the tissue microenvironment and one of the main regulators of cell cross-talk in response to microenvironmental stimuli. The unique characteristics of the ECM are genuine characteristics of EC and UF. For example, some components of the ECM, such as aggrecan, nidogen, α1-chain collagen type VIII, and α2-chain collagen type XI, are elevated in stage III EC. However, the molecular, cellular, and mechanical features of the ECM at different stages of disease initiation and progression, from a normal endometrium to precancerous and malignant EC tissue, remain elusive ^[43][91]. Generally, any fibrosis is attributed to excessive deposition of the ECM ^[44][92] and changes in its composition and mechanical characteristics. In the case of UF, the composition of the ECM changes, and the contents of collagen 1A1, fibronectin, and versican in the ECM increase ^[45][93]. The aberrant ECM of UV contributes to its pathogenesis, at least as it has been demonstrated in relation to the role of directed ECM mechanotransduction and the central part of ECM rigidity in the pathogenesis of UV ^[46][94]. Pulmonary fibrosis caused by SARS-CoV-2 infection is very well-understood and its mechanisms can be extrapolated to UF to some extent. However, the tissue microenvironment of UF is unique in terms of its ECM, immune-cell infiltration, the hormonal environment and its changes, and so on. The literature has demonstrated that COVID-19 significantly affects ECM remodeling in lung tissue ^[47][48][95,96], but long-term effects on the FRS, including in EC and UF, are unknown and should be investigated.

4. Impact of COVID-19 on the Genome and Epigenome

A sufficient amount of data has been accumulated about COVID-19 through the serum of patients ^[49][104], showing that increased levels of growth factors affect gene expression ^[50][86]. There are differences in endometrial gene expression in women with coronavirus disease 2019 ^[51][107]. The SARS-CoV-2 spike glycoprotein shares 41 minimal immune determinants, i.e., pentapeptides, with 27 human proteins that are associated with oogenesis, uterine receptivity, decidualization, and placentation. All but four of the common pentapeptides we have identified are also present in epitopes derived from the SARS-CoV-2 glycoprotein, which have been experimentally confirmed to be immunoreactive ^[52][108]. Noncoding RNA (ncRNA) plays a fundamental role in various biological processes associated with the pathogenesis of endometrial cancer, and many varieties also have a prognostic function, which is of great importance for determining therapeutic pathways and patient follow-up. Personalized medicine focuses on constantly updating risk factors that are identified in the early stages of endometrial cancer in order to tailor treatment to patients ^[53][54][109,110]. Regulatory noncoding RNA (NCRNA), such as miRNA (miRNA) and long noncoding RNA (lncRNA), plays a vital role in EC oncogenesis and UF pathogenesis ^[46][55][94,111] and can therefore be used as EC/UF biomarkers or therapeutic targets. Many varieties may be affected by COVID-19. It has been reported that some microRNA can modulate TGF-β pathways in UF and myometrial cells ^[56][112], so it would be interesting to evaluate its levels during and after COVID-19. Interestingly, one recent paper identified several miRNAs differentially expressed in individuals affected by COVID-19, and KEGG pathway-enrichment analysis identified the endometrial cancer pathway (hsa05213) as one of the common pathways for miRNA to up- or downregulate COVID-19 ^[57][113]. SARS-CoV-2 has been shown to cause DNA damage and general genome instability ^[58][59][114,115], well-known hallmarks of cancer and driving forces behind tumorigenesis. COVID-19 may be a risk factor. A recent publication demonstrated that an increased risk of COVID-19 is associated with an increased risk of EC ^[60][116]. Studies of genetic susceptibility to UF suggest that genes involved in regulation of genome stability may somehow contribute to the pathology of UF ^[61][117], while COVID-19, as discussed above, leads to genome instability. Interestingly, individuals with UF often carry mutations in MED12 gene-encoding subunit 12 of the mediator complex (MED12) ^[62][118]; such mutations have been shown to be present in UF stem cells but not in stem cells of adjacent normal myometria, and stem cells of UF with mutations in MED12 have shown increased DNA damage ^[63][119]. Other studies have shown that MED12 is simultaneously associated with DNA damage repair (DDR) and is found in the SARS-CoV-2 protein interactome ^[64][120]. Thus, it is possible that COVID-19 will exacerbate UF. It has recently been demonstrated that SARS-CoV-2 disrupts chromatin regulation in infected cells ^[65][121]. At the same time, UF is characterized by epigenetic changes, such as insufficient deposition of histone H2A.Z, which leads to disruption of the differentiation program in cells ^[66][122]. H2A.Z is also critical for repair of double-stranded DNA damage ^[67][123]. In EC, the chromatin-remodeling and DDR genes are also frequently mutated, which is described in detail elsewhere ^[68][124] and is therefore beyond the scope of this resviearchw. Overall, it can be hypothesized that SARS-CoV-2, through its interference with the chromatin structure and DDR molecular machinery, may “aggravate damage” in DDR-compromised cells.