Starting Infection

[Publication date of latest article cited: October 26, 2023]

The number of pathogens entering the body that can start infection is called the “infectious dose.” Scientists’ estimates of the infectious dose for SARS-CoV-2 in hamsters,ferrets, an humans range between 5 (Rosenke et al.), 10 (Bazant & Bush), or 100 (Karimzadeh et al.), or 60,000 (Poydenot et al.).  When measured in plaque forming units (PFU), an indirect way of quantifying viruses, as low as 1.8 X 10³ PFU infected hamsters (Monchatre-Leroy et al.), and 500 PFU infected a ferret  (Qiu G, Zhang X, et al.; Ryan et al.). If many less than that enter, the immune system can probably fight them off.  If many more than that enter, then that might cause greater numbers of the viruses to multiply in the body, which might cause more severe disease in some people (Karimzadeh et al.; Mandavilli “It’s not whether”; Spinelli et al.). If this occurs over 15 consecutive minutes, or a cumulative 15 minutes in one day, it can cause infection (Centers for Disease Control and Prevention “Coronavirus Disease 2019 (COVID-19) Appendices”; Pringle et al.).  The new Delta variant is more transmissible than the original version of SARS-CoV-2, because Delta causes higher viral loads (the density of viruses in the infected body) and shorter incubation periods (Reardon; Wang Y, Chen R, et al.; Zhang M, Xiao J, et al.).

Spike proteins on the outside of the virus attach to a protein called angio-tensin converting enzyme 2 (ACE2) on the outside of some kinds of human cells.  ACE2 normally regulates other molecules on the cells, and maintains blood pressure, electrolyte and fluid balance, and allows inflammation and apoptosis cell death (Alshamarry et al.; An et al.; Gintoni et al.; Liu Y, Wu Q, et al.; Ornes; Salamanna et al.; Salas Orozco et al.; Saville et al.; Scudellari “How the coronavirus Infects cells”).  The virus also exploits other molecules on the outside of human cells to enter the cells, especially transmembrane protease serine 2 (TMPRSS2), which normally helps the cell take proteins apart, so the cell can use the amino acid parts to make other proteins.  To enter cells, this virus also uses transmembrane protease serine 4 (TMPRSS4), which normally helps to bind proteins (Katopodis et al.; Salamanna et al.; Salas Orozco et al.; Saville et al.; Scudellari “How the coronavirus Infects cells”).   The virus’s spike protein also binds to neuropilin-1 (NRP1) on the outside of cells, in order to enter the cells, which are abundant inside the nose (Cantuti-Castrelvetri et al.; Daly et al.; Kielian; Salamanna et al.; Salas Orozco et al.; Shojaee et al.).  The protease furin normally helps take proteins out of cells (Molloy et al.; Stockli et al.).  After SARS-CoV-2 binds to a cell, it uses furin to enter the cell (Peacock et al.; Salamanna et al.).  So, SARS-CoV-2 infects cells which have ACE2, TMPRSS2, NRP1, furin, and other proteases.  The viruses replicate in the cell’s endoplasmic reticulum (ER) and Golgi complex, exits the cell, and causes cell death which results in COVID-19 disease (Alshamarry et al.; Saville et al.; Scudellari “How the coronavirus Infects cells”).

Genes associated with cells having molecules susceptible to SARS-CoV-2 are in the nose, mouth, lungs, heart, intestines, nerves, kidney, placenta, testes, and prostate, especially the epithelial cells inside these organs which are exposed to the outside air (Huang N, Pérez, et al.; Salamanna et al.; Shojaee et al.; Singh et al. “A Single Cell RNA Expression Map. Cornell”;  Singh et al. “A Single Cell RNA Expression Map. Cell Reports”; Wiegand), and the pulmonary endothelial cells (Gintoni et al.).  Fewer ACE2 and TMPRSS2 molecules are on the endothelial cells exposed to internal channels, such as blood vessels, so SARS-CoV-2 probably cannot infect them (Flaumenhaft et al.; Schimmel et al.).  The genes controlling ACE2 vary; some genotypes are associated with more severe disease (Gintoni et al.).

Mouth, Nose, and Respiratory System

[Publication date of latest article cited: August 2, 2023]

When someone inhales SARS-Cov-2 in droplets and aerosols, the viruses can infect the cells inside the mouth and nose, which have much ACE2 and other receptors (Hamming et al.; Huang et al.; Li H, Wang Y, et al.; Nazaroff; Ortiz et al.; Salamanna et al.; Salas Orozco et al.; Singh et al.“A Single Cell RNA Expression Map Cell Reports”; Wang C, Prather K, et al.; Zhong M et al.).  People can also put SARS-CoV-2 inside their noses by touching the inside of their noses (Lavell et al.).  SARS-CoV-2 can infect salivary glands, which can produce saliva with SARS-CoV-2 (Zhu F, Zhong Y, et al.), which can then infect another person via droplets and aerosols. SARS-CoV-2 infects and destroys large numbers of nose cells, reducing the ability to smell, called anosmia (Shamsundara et al.). SARS-CoV-2 can float past the cilia and mucous membranes, enter the lungs, and infect the alveoli air sacs (Meselson; Nazaroff; Wang C, Prather K, et al.).  The circulatory system can then carry SARS-CoV-2 to the intestines, lungs, and other organs having ACE2 (Flaumenhaft et al.; Hamming et al.; Ortiz et al.; Salamanna et al.; Salas Orozco et al.; Singh et al. “A Single Cell RNA Expression Map Cornell”; Singh et al. “A Single Cell RNA Expression Map Cell Reports”; Yang et al.).  SARS-CoV-2 replicates competently in bronchus and lung cells (Hui et al.).  Infected people of all ages have the viruses in their nasopharynx (nose and throat), but small children have more of the viral RNA, indicating (but not completely proving) that they might transmit to others more than older children and adults transmit (Heald-Sargent et al.).  So, the infection usually starts in the nose and eyes, spreads through the respiratory system, and then to many organs (Chen M, Shen et al.; Fischetti et al.; Johns Hopkins Medicine; Matheson, Lehner; Nature; Wadman et al.; Wiersinga et al.; Zhou L, Xu, et al.).

SARS-CoV-2 multiplies rapidly in the epithelial and endothelial cells in the internal surfaces of the respiratory system. SARS-CoV-2 binding to ACE2 may contribute to vasoconstriction, oxidative organ damage, and white blood cells releasing proteins called cytokines rushing into the lungs.  Excessive reactions like this inflame and damage alveoli air sacs, called a “cytokine storm” (Allegra et al.; Flaumenhaft et al.; Gintoni et al.; Tavasolian et al.; Ye et al.).  SARS-CoV-2 in the respiratory system are shown in eye-catching photos of hundreds of the virions (whole infectious viruses) on the cilia (hair-like cells), taken by researchers (Ehre; University of North Carolina).

Eyes

[Publication date of latest article cited: September 2, 2023]

SARS-CoV-2 can probably transmit via aerosols and droplets into eyes, infecting them, and spreading into the respiratory system (Coroneo, Collingnon; Li H, Wang Y, et al.; Matos et al.; Roshanshad et al.; Singh K, Pattebahadur et al.).  Many people spontaneously touch their hands to their eyes often, which could spread SARS-CoV-2 and other pathogens (Carrillo-Diaz et al.; Spencer et al.).  In some COVID-19 patients, SARS-CoV-2 might have entered the eyes of those who had not been wearing face shields (Chen X, Yu H, et al.; Lu CW, Liu, et al.).  Some patients had ocular symptoms (sore eyes, eye irritation, conjunctivitis) before and during having COVID-19 symptoms in other body parts (Hong N, Yu, et al.; Leung, Fan, et al.; Pardhan et al.; Singh K, Pattebahadur et al.).  RT-PCR found SARS-CoV-2 in the tears and conjunctival secretions of some patients with dry eyes and conjunctivitis (Aiello et al.; Chen L, Liu M et al.; Chen MJ, Chang, et al.; Chen X, Yu H, et al.; Ciloglu et al.; Karia et al.; Singh K, Pattebahadur et al.; Wu P, Duan, et al.; Xia et al.; Zhang X Chen, et al.), and some patients without eye symptoms (Singh K, Pattebahadur et al.; Xie et al.).  SARS-CoV-2 replicates competently in conjunctiva  (Chen X, Yu H, et al.; Hui et al.).  The flow of tears to the nasolacrimal system, and the innate immune system, can prevent most pathogens from entering the eyes.  But if SARS-CoV-2 gets past that, and infect some eye cells via their ACE2 receptors (Leung, Fan, et al.; Salamanna et al.; Zhou L, Xu, et al.), then viruses could flush with tears into the nasopharyngeal space in the nose and throat, and then to the respiratory system (Chen X, Yu H, et al.; Coroneo, Collingnon; Hong N, Yu, et al.; Napoli et al.).   These events can occur in both children and adults (Beery).  SARS-CoV-2 was in tears of 24% of moderate to severe patients (Arora et al.), indicating they potentially could transmit to other people.  For these reasons, COVID-19 might be transmitted from an infected person’s eye to others.

Wearing glasses is statistically associated with not getting COVID-19 in several studies during the pandemic, indicating that perhaps glasses prevent SARS-CoV-2 from entering eyes (Maragakis; Parker-Pope “Does Wearing Glasses Protect”; Zeng W, Wang, et al.). But, a randomized clinical trial among people of whom 77% were vaccinated against COVID-19, found that those assigned to wearing glasses did not have a statistically significant different number of COVID-19 infections, but had lower incidence of other respiratory infections (Fretheim et al.). This shows that wearing glasses had little effect on COVID-19 vaccinated people.

So, people can protect their eyes from SARS-CoV-2 by avoiding touching near their eyes, and wearing face shields, safety glasses, or goggles (Chen MJ, Chang, et al.; Chen X, Yu H, et al.; Coroneo, Collingnon; Leung, Fan, et al.; Lu CW, Liu, et al.; Napoli et al.; Wu P, Duan, et al.). In response to the pandemic, eye care professionals are taking more precautions in working with patients and biological samples (Salvetat et al.).

Stomach

[Publication date of latest article cited: February 14, 2023]

Fecal-oral transmission possibly contributes to SARS-CoV-2 transmission (Cuicchi et al.; de Oliveira GLV, Oliveira, et al; Giron-Navarro et al.; Gwenzi; Heneghan, Spencer “SARS-CoV-2 and the role of orofecal transmission”;  Jones DL et al.; Li H, Wang Y, et al.; Mohan et al.; Parsa et al.; Qian Q, Fan; Wang Y et al; World Health Organization-China; Wong et al.; Xiao F, Tang M, et al.).  Almost all people defecate in toilets, so it is unlikely that SARS-CoV-2 often went from feces to foods.  SARS-CoV-2 probably entered most patients’ respiratory system, then circulatory, then digestive system (Anelich et al.; Amirian; Wadman et al.).  But stomach and intestinal cells have ACE2 and TMPRSS2, which SARS-CoV-2 uses to enter cells and cause SARS-CoV-2 shedding in feces in about half of COVID patients (An et al.; Cao et al.; Friedel et al.; Liu Y, Wu Q, et al.).

Some evidence shows that SARS-CoV-2 may have transmitted orally through the stomach in some patients (Friedel et al.).  People who took proton pump inhibiter (PPI) medicines (which reduce stomach acidity) were more likely to test positive for COVID-19 (Charpiat et al.), or rotaviruses, influenza, norovirus, and Middle East Respiratory Virus (MERS) (Almario et al.), than those who did not take PPI.  This indirectly implies that stomach acid is protecting many people from COVID-19 and those other diseases in the gastrointestinal system. But another study did not find a correlation with PPI use (Miyake et al.).  SARS-CoV-2 has a rigid outer shell and low shell disorder, which could enable fecal-oral transmission (Gwenzi).

Another indirect indication that SARS-CoV-2 could infect the stomach and intestines is that COVID-19 patients were more likely to have intestinal metaplasia (IM), in which stomach lining cells become similar to intestinal epithelial cells.  Some of those patients also had a history of  H. pylori infection, which can cause IM.  Some had enterocytes with ACE2 and TMPRSS2 in their gastric mucosa, the receptor molecules that SARS-CoV-2 uses to enter cells (Zhang M, Feng, et al.).

A study tested these hypotheses by challenging Rhesus monkeys with SARS-CoV-2 intragastrically or intranasally.  They found the resulting infections partly similar.  This shows that SARS-CoV-2 entering the stomach can cause infection (Jiao et al.; Meng, Liang).

SARS-CoV-2 probably can replicate in stomach cells.  Scientists modeled this in vitro by generating gastric organoids (mini organs from cells in adult, pediatric, and fetal biopsies).  They then infected the organoids, and cultured the resulting viruses (Giobbe et al.).

Whether this can happen in a live person depends on if stomach acid inactivates SARS-CoV-2.  The related SARS-CoV-1 is inactivated at acidic pH 1 – 2 (Darnell et al.; Scheller et al.).  SARS-CoV-2 was stable at moderate pH 3 – 10, but that study did not test it at more acidic or basic pH (Chin AWH, Chu JTS, et al.).  Since these two viruses are mostly similar, SARS-CoV-2 is probably inactivated by acids.  So, it probably cannot pass through the stomach gastric acid (Pressman et al.), when it is usually pH 1.5 – 3.0 (Cole, Kramer).  But a full meal can neutralize stomach contents to pH 6, which might allow SARS-CoV-2 to pass (Konturek et al.).  Scientists should conduct more experiments to find if SARS-CoV-2 is inactivated by pH<3, and by human gastric acid at its full range, 1.5 to 6.  Then they could make more definite statements about whether SARS-CoV-2 can pass through the stomach and cause fecal-oral transmission.

Sexual Organs

[Publication date of latest article cited: August 20, 2023]

COVID-19 is probably not sexually transmitted, but hypothetically it might rarely occur (Duarte et al.; Entezami et al.; He W, Liu, et al.; Hezavehei et al.; Tur-Kaspa et al.; Yan et al.).  Some studies found SARS-CoV-2 RNA in semen, which shows it might infect another person (He W, Liu, et al.; He Y, Wang J, et al.; Karia et al.; Li D, Jin, et al.; Saylam et al.). But others did not find it in semen and expressed prostatic secretions (EPS) of infected men (Entezami et al.; He W, Liu, et al.; He Y, Wang J, et al.; Pan F, Xiao et al.; Pavone et al. ).  A study tested vaginal fluid and cervical exfoliated cells of infected women, and found no SARS-CoV-2 RNA (Cui et al.).  ACE2 is expressed in testes, prostate glands, and spermatids in men (He W, Liu, et al.; He Y, Wang J, et al.; Hezavehei et al.; Salamanna et al.; Tur-Kaspa et al.; Vahedian-Azimi et al.), and uterus, ovaries, fallopian tubes, vagina, and placenta in women (Gesaka et al.; Salamanna et al.; Yan et al.; ).  But most of these organs lack TMPRSS2, which these viruses also use to enter cells (Tur-Kaspa et al.). TMPRSS4 is also expressed in the vagina, cervix, fallopian tubes, ovaries, uterus, and breasts (Katopodis et al.).

COVID-19 has harmed some mens’s reproductive organs (Abedinzadeh et al.; He Y, Wang J, et al.; Hezavehei et al.; Moshrefi et al.; Tur-Kaspa et al.).  There is more ACE2 in testes than ovaries, so testes might serve as reservoirs for SARS-CoV-2, which might explain why more men were severely infected than women (Entezami et al.; Hamming et al; He W, Liu, et al.; Moshefri et al.).  COVID-19 infection has impaired sperm production in some men (He Y, Wang J, et al.; Hezavehei et al.; Li H, Xiao et al.; Moshrefi et al.).   But it is uncertain if this was caused by fever (Bendayan, Boitrelle; He Y, Wang J, et al.), or if anti-viral drugs ( Hezavehei et al.) or SARS-CoV-2 infection immune reactions damaged the testes and related tissues (He Y, Wang J, et al.; Zafar, Li).  SARS-CoV-2 could cause problems for natural reproduction or assisted reproduction technologies (ART) (Entezami et al.; He W, Liu, et al.; Moshrefi et al.; Tur-Kaspa et al.).

Males and females have different degrees of molecular interactions with SARS-CoV-2 infections. Men have more androgen, which activates ACE2 and related molecules in the renin-angiotensin system (RAS), causing hypertension, inflammation, vasoconstriction, fibrosis, and cell proliferation.  But estrogen causes the opposite reactions.  Males’ androgen receptor (AR) may allow SARS-CoV-2 to use TMPRSS2 to enter more cells.  Women may have better T cell responses to SARS-CoV-2 (Galbadage et al.).

Even if COVID-19 is probably not transmitted by sexual intercourse, sexual interactions could transmit it through other routes described above (Cipriano et al.).  The least risky approach would be abstinence, higher risk is partners living together, or regular partners not living together. The next higher risk approach is partners not living together using face masks.  Highest risk is having several partners not using masks (Marcus; Turban, Keuroghlian, Mayer; Tam).

Pregnancy, Newborns, and Breast Feeding

[Publication date of latest article cited: September 19, 2023]

When COVID-19 infected pregnant women gave birth, almost all infants were not infected (Akhtar et al.; Chen H, Guo, et al.; Chen Y, Peng, et al.; de Oliveiro, de Oliveiro, Wernet, et al.; Edlow et al.; Jamieson, Rasmussen; Kumari et al.; Simões e Silva, Leal; Sturrock et al.). Small numbers were infected briefly, however, indicating possible intrauterine vertical transmission from the mother through the placenta to the fetus (Gale et al.; Gesaka et al.; Jamieson, Rasmussen; Kelvin and Halperin;  Makvandi et al.; Malshe et al.; Mullins et al.; Parums; Qiao; Saadaoui et al.; Song et al.; Van Beusekom “COVID19”; Yu N, Li et al.; Zeng L, Xie, et al.; Zhang Z, Yu, et al.).  Most of those infected during pregnancy soon recovered (Rodriguez; Sturrock et al.; Vivanti et al.). Risk of neonatal or infant death with maternal SARS-CoV-2 infection was not higher than those of uninfected mothers ( Sturrock et al.).  Some fetuses died when SARS-CoV-2 damaged the placenta and umbilical cord, causing the fetus to asphyxiate even though the viruses did not enter the fetus (Dubucs et al.; Stonoga et al.); or caused excessive fluid buildup in the fetus (Dubucs et al.; Shende et al.); or replicated in organs and induced thrombosis (Greco et al.).

Some cells and tissues between pregnant women and their fetuses (the maternal-fetal interface) and some fetal organs had angiotensin-converting enzyme 2 (ACE2) receptors, which SARS-CoV-2 uses to enter cells (Li M, Chen l et al.; Saadaoui et al.; Salamanna et al.). Some placentas of SARS-CoV-2 infected infants had SARS-CoV-2 in the fetal side, showing that those viruses could infect some fetuses (Caparros-Gonzalez et al.; Facchetti et al.; Gesaka et al.; Patanè et al; Schwartz, Thomas; Shende et al.; Vivanti et al.).  But other studies found that human placentas lack ACE2 receptors and transmembrane protease TMPRSS2 which SARS-CoV-2 also uses to enter cells (Meštrović; Pique-Regi et al.).  Some umbilical cord, amniotic fluid, and other fluid samples also had SARS-CoV-2 RNA (Caparros-Gonzalez et al.; Stonoga et al.).  The mothers’ T cell responses to SARS-CoV-2, and inefficient SARS_CoV-2 replication in placentas could be preventing intrauterine infections (Tallarek et al.).  So, scientists found that intrauterine transmission rarely went through the placenta, but they do not yet fully understand the biochemical processes.

Early in the pandemic some doctors recommended that pregnant women with COVID-19 have caesarian births, not breastfeed, and stay away from their infants.  But studies showed that among women infected with COVID-19 while pregnant, the low rates of infant infection were about the same whether the baby was born vaginally or by caesarian, breastfed or not, or stayed with the mother or not (Gale et al.; Walker KF, O’Donoghue et al.).

Breast milk probably does not transmit SARS-CoV-2.  Among women breast feeding while infected with COVID-19, few or no milk samples had SARS-CoV-2 RNA (Caparros-Gonzalez et al. Centeno-Tablantes et al.; Chambers et al.; Luo QQ, Xia L, et al.; Gesaka et al.; Pace et al.; Saadaoui et al.).  When tested, none had viruses that could replicate.  When milk with SARS-CoV-2 was treated with Holder pasteurization, RT-PCR found no RNA afterwards.  This shows that it was safe for others to use, such as in milk banks (Chambers et al.).  Many milk samples had IgA , IgM, or IgG antibodies, some of which could neutralize SARS-CoV-2, providing some immunity to the baby (Luo QQ, Xia L, et al.; Morniroli et al.; Pace et al.).  One mother had SARS-CoV-2 in her breast milk for 4 days, and her newborn was briefly infected.  It was unclear how the newborn was infected (Groß et al.).  If a mother is exposed or infected while breastfeeding or pumping milk, she can probably safely continue to feed her infant (Luo QQ, Xia L, et al.), because breast milk includes antibodies to SARS-CoV-2.  She should clean her breast or pump to prevent transmitting this virus via those surfaces (Pace et al.; Sullivan S, Thompson).

After a  baby is born, the mother and her family could transmit viruses to the baby by the same routes as any other person.  So, they should use the same prevention methods as for an adult.