In the last 3 weeks we have been receiving reports from a numerous physicians in the United Kingdom, South Africa, United States, Australia the incidences of individuals who had tested positive for COVID-19 but in most cases only displaying asymptomatic or mild symptoms, reporting days later of developing genital and anal warts that later tested positive for the HPV virus (human papillomavirus) via DNA test.
Some had also developed the usual symptoms associated with warts caused by HPV including pain, irritation and in some cases bleeding. The incidences were seen in both otherwise healthy women and men.
Immune Dysregulation Promoted by SARS-CoV-2 Can Lead to Reactivation of Already Acquired Neurotrophic Pathogens Such as Herpesviruses
Another possible scenario for persistent symptom development in some PASC patients is that SARS-CoV-2 may fully clear from patient blood, tissue and nerves after acute infection.
However, the virus may dysregulate the host immune response during acute COVID-19 in a manner that allows previously harbored pathogens to reactivate, infect new body sites, and drive new chronic symptoms.
It is well understood that humans accumulate persistent viruses over the course of a lifetime. These viruses generally persist in dormant, latent, or non-cytolytic forms, but may reactivate under conditions of stress or immunosuppression. Indeed, people regarded as healthy have been shown to harbor a wide range of persistent viruses in blood, saliva (Wylie et al., 2014), or tissue that are capable of activation under such conditions (Virgin et al., 2009).
For example, Kumata et al. (2020) took RNA-seq data from the Genomic-Tissue Expression Project: a public resource created to study tissue-specific gene expression/regulation from 51 tissue types collected from 547 healthy individuals at autopsy. They successfully identified 39 viral species in at least one tissue (tissue types included brain, pituitary, esophagus, thyroid, heart, breast, lung, kidney, adrenal gland, prostate, nerve, adipose tissue, blood vessel, ovary, and uterus).
Viruses identified in the various tissue samples included Epstein-Barr virus (EBV), herpes simplex virus (HSV-1), varicella zoster virus (VZV), cytomegalovirus (CMV), human herpes virus 6-A/B (HHV6-A/B), human herpes virus 7 (HHV-7), hepatitis C virus (HCV), human papilloma virus (HPV), adeno-associated virus and RNA viruses including respiratory syncytial virus (RSV), and parainfluenza virus 3.
Human coronavirus 229-E was identified in brain, thyroid, heart, lung, stomach, adrenal gland, skin and blood samples. The team stated: “We found that the human virome includes several viruses ‘hidden’ by expression/replication in tissues inside the human body without being abundant in the blood.”
Kumata and team also characterized how viruses they identified associated with human gene expression and immune activity. As a general trend, gene expression and immune changes correlated with viral presence in a tissue were associated with components of the immune response known to control pathogen activity. For example, genes associated with “type 1 interferon signaling pathway,” “defense response to virus,” and “viral process” were highly upregulated in hepatitis C virus liver tissue samples.
This suggests that persistent viruses are normally kept “in check” by the host immune system. However, if the immune response is weakened, challenged, or dysregulated, the same viruses may change their gene expression or protein production to drive a range of persistent symptoms.
For example, more than 90% of humans harbor at least one strain of herpesvirus (Gacek, 2002), but most infections are kept in latency by host interferons (Decman et al., 2005; Le-Trilling and Trilling, 2015). However, by disabling the host interferon response, (Acharya et al., 2020), SARS-CoV-2 may allow persistent herpesviruses to take advantage of acute COVID-19.
Early studies and case histories demonstrate that herpesviruses are indeed reactivating in COVID-19 patients (Chen et al., 2020; García-Martínez et al., 2020). For example, Xu R. et al. (2020) reported VZV and HSV-1 reactivation in a patient with severe COVID, which correlated with the onset of septic shock. Another team demonstrated reactivation of HHV-6, HHV-7, and EBV in patients with acute COVID-19 (Drago et al., 2021).
Herpesvirus infection has been tied to the development of many different chronic disease states. For example, EBV, CMV, and Kaposi’s sarcoma-associated herpesvirus (KSHV) are recognized as cancer-causing or oncogenic viruses (Luo and Ou, 2015). These and related viruses such as hepatitis B virus (HBV), HCV, and papillomavirus can drive diseases like cancer by expressing proteins that directly modulate human gene expression, the human immune response, host cell metabolism, and even the host epigenetic environment to promote a range of pathological processes (Proal et al., 2017).
For example, EBV can express protein EBNA2. One study found that EBNA2 and its related transcription factors can bind and activate human genes associated with the development of dozens of chronic conditions including multiple sclerosis, rheumatoid arthritis, type 1 diabetes, and celiac disease (Harley et al., 2018).
In fact, the team demonstrated that EBNA2 directly binds half of the locations on the human genome known to contribute to lupus risk. EBV protein EBNA3 has been shown to bind to the human vitamin D nuclear receptor (VDR) to block activation of its target genes (Yenamandra et al., 2010). Since the VDR controls the expression of hundreds of human genes, including several that regulate key components of the innate immune response such as TLR-2 and the cathelicidin antimicrobial peptides (Wang et al., 2005), this disruption can have far reaching negative consequence for overall host immune function.
Epstein-Barr virus can also hijack the metabolism of the cells it infects. For example, Wang et al. (2019) found that, in infected primary human B cells, EBV upregulated host mitochondrial 1C metabolism. Expression of EBV proteins, and not the host cell innate immune response, was required for this 1C induction.
Indeed, all viruses, and many bacterial and fungal pathogens, hijack the metabolism of the cells they infect in order to gain amino acids, lipids, and other substrates required for their own replication and survival (Escoll and Buchrieser, 2018; Thaker et al., 2019; Proal and VanElzakker, 2021). Dozens of human pathogens capable of persistence modulate the activity mitochondrial electron chain complexes (Escoll et al., 2019). This leads to bioenergetic and metabolic alterations in infected host cells that dysregulate oxidative phosphorylation levels and even regulation of cell death.
Persistent viruses that activate under conditions of SARS-CoV-2-driven immunosuppression or immune dysregulation might also infect new body sites and cell types, allowing them to drive new symptoms. Both herpesviruses and enteroviruses are neurotrophic pathogens, with the herpesvirus active life cycle relying on moving through nerves (Steiner et al., 2007; Huang and Shih, 2015).
It follows that under conditions of immunosuppression, they can move out of blood, saliva, or tissue and deeper into the CNS. Once in the CNS, such viruses have been shown capable of driving a range of neuroinflammatory processes. For example, HHV6 and HHV7 were recently identified in autopsied Alzheimer’s brains, where they regulated host molecular, clinical, and neuropathological networks in a manner that contributed to inflammation and neuronal loss (Readhead et al., 2018). HHV-6 was shown to accelerate neuroinflammation in a non-human primate model of multiple sclerosis (Leibovitch et al., 2018).
In some cases, even latent viruses express proteins capable of driving chronic symptoms. For example, elevated cytokine expression in response to HSV-infected peripheral nerve ganglia was shown to persist even when the virus remains in a latent, non-replicating state (Chen et al., 2000). Similarly, SITH-1, a protein expressed during HHV-6B latency, has been connected to HPA axis dysregulation and increased risk of depression (Kobayashi et al., 2020).
reference link : https://www.frontiersin.org/articles/10.3389/fmicb.2021.698169/full