Infections Locations and Disease Patterns

[in work]

• Introduction to Coronavirus Disease Patterns
• Infections Locations of Human Coronaviruses
  • Overview
• Infection Locations by Coronavirus Species
  • Infection Locations of SARS-1
  • Infection Locations of MERS
  • Infection Locations of SARS-2
  • Empirical Deduction
  • Diseases caused by Bovine Coronavirus
• How to Determine Infection Locations of Coronaviruses
  • Infection Locations and Immune Responses
• References and Resources
  • Viral Load at the Different Infection Locations for SARS-2
  • Pathogenesis and Viral Load for Coronaviruses
  • Covid-19 Symptoms depending on Infection Pathway
  • Expression Locations of ACE2
  • Disease Pattering for Influenza
• Appendix
  • ACE2 Receptor
  • On the Origin

Introduction to Coronavirus Disease Patterns

Coronaviruses cause infections and thereby induce induce different diseases:

• The human endemic coronaviruses (OC43, HKU1, NL63 and E229) usually infect the middle or upper respiratory tract.
• The coronaviruses directly emerging from zoonoses MERS-CoV and Sars-CoV-1 mainly infect the lower respiratory tract and sometimes the intestine.

In the case of bovine coronaviruses it is observed that the same strains cause different diseases depending on the outbreak:

• Enteric disease (neonatal calf diarrhea, winter dysentery)
• Respiratory disease (shipping fever and general pneumonia).

Till the 90’s it hasn’t even been clear that both are cause by the same coronavirus since they occur often independent and usually do not transform into each other.

Similarly to bovine coronaviruses, the human coronavirus NL63, which usually causes upper respiratory tract infections, from time to time is involved in an outbreak cascade of lower respiratory tract infections. E.g. observed in old care homes [citation in work].

For Sars-CoV-2, different infection patterns are observed: Virulent lower respiratory tract infections, similar to Sars-CoV-1 and MERS-CoV and subtle and often mild middle or upper respiratory tract infections similar to the four endemic coronaviruses. This yields the questions:

• What drives and causes the different infection location patterns?
• How to prevent and treat depending on locations?
• Which are complications and risks?
• What immune protections are raised in which circumstances.

Regarding these questions the following hypotheses are stated and argued:

• Coronavirus can induce distinct infection patterns
• The infection patterns are the result of and can be predicted by the factors:
  • the RNA sequence
  • the exact building blocks (mainly envelope lipids) and state of the virions (spike priming) which depend on the history of the initial virion[s] i.e. the cell and location they got produced and the physical, chemical and biological factors they have been exposed on their travel
  • the initial infection location
  • the host immune system and its experience with the virus strain
• The pathogenesis, possible complications and the optimal treatment depend on the infection patterns.

Infections Locations of Human Coronaviruses

Abbreviations

• LRI = lower respiratory tract infection (bronchioles, alveoli)
• MRI = middle respiratory tract infection (bronchi, trachea)
• URI = upper respiratory tract infection (pharynx = throat, mouth, nose)
• EI = enteric infection (intestine)

Overview

The coronaviruses directly emerging from zoonoses from outdoor living animals MERS-CoV and Sars-CoV-1 infect the LRI and often spread to the intestine. The coronaviruses well adapted to our ‘modern’ way of life with dense population and in indoor rooms mainly infect to upper respiratory tract and ignore the intestine (Thoughts on the origin).

Infection Locations by Coronavirus Species

Infection Locations of SARS-1

The only location where all patients had viral Sars-CoV-1 load are the lungs Farcas et al.

Infection Locations of MERS

For MERS-Cov Memish et al. found that both the viral load and the Genome Fraction obtained was higher in the lower respiratory tract (broncho-alveolar lavage fluid, tracheal fluid) than in the upper respiratory tract (nasopharyngeal swab, sputum). The three broncho-alveolar lavage fluid samples investigated, showed the highest average viral load and contained the most complete genome. Remark: Mers-Cov has a different cell entry receptor (DPP4). However

• the ability of a virus to efficiently takeover a cell depends not on the cell entry receptor alone.
• some and especially the severe SARS-2 infections show a similar pathogenesis as MERS

Infection Locations of SARS-2

Theoretical Deduction

• Entry Point: Depending on the transmission form of SARS-2.Virions enter through the respiratory tract In the following the infections of Sars-CoV-2 are deduced from the cell tropism and the reachability of the tissue in question.

Empirical Deduction

[in rework: update and a section for each strain] The viral loads measured in combination with the movements of virions inside the body can be used to backtrack tissue habitats of Sars-CoV-2. [in work]

Diseases caused by Bovine Coronavirus

[raw form is on todo-list]

How to Determine Infection Locations of Coronaviruses

The task determine to habitat of Sars-CoV-2 can be tackled either

• Theoretical Deduction taking into account the following topics:
  • Entry Point: Where to virions enter initially.
  • Tropism: The ability of the entered virions to infect different cells and tissues. The tropism in turn are based on in vivo and in vitro experiments and empirical observations.
  • Kinetics: How produced virions are moved to reach new infectable cells and tissues.
  • Local Immune System: the local immune surveillance.
• Empirical Deduction based on observations of Covid-19 cases by diagnostic methods:
  • Measuring the viral load at different locations (Sometime the viral load needs to be corrected for the movement of virions.)
  • Detect tissue damage typical for viral infections and check e.g. by PCR the damage was indeed induced by a SARS-2 infection.

[in work]

Infection Locations and Immune Responses

[in work and partly estimated/guessed, citations coming/in search]

Not Infectable Locations

Not infectable since no ACE2 and thus the symptoms from the corresponding location indicate an agent other than Sars-2

[todo: merge with infection locations and add ‘infectable column’ e.g. ace2 column]

References and Resources

Viral Load at the Different Infection Locations for SARS-2

Yang

Laboratory Diagnosis and Monitoring the Viral Shedding of SARS-CoV-2 Infection Summary of Yang et al on the page diagnosis_and_viral_load.md

Mazumder

Summarized Review Mazumder on the page diagnosis_and_viral_load.md

Woelfel

Virological assessment of hospitalized patients with COVID-2019

• Figure 2: Viral load kinetics in Swab, Sputum and Stool and seroconversions

Pathogenesis and Viral Load for Coronaviruses

Su,Bi,Gao

Review Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses; S Su, Y Bi, G Gao et al

• Table 1: comparison of the infection caused by the HCoVs 229E, OC43, Sars-CoV, NL63, HKU1, MERS-CoV

memish

Ziad A. Memish, Jaffar A. Al-Tawfiq, Hatem Q. Makhdoom, Abdullah Assiri, Raafat F. Alhakeem, Ali Albarrak, Sarah Alsubaie, Abdullah A. Al-Rabeeah, Waleed H. Hajomar, Raheela Hussain, Ali M. Kheyami, Abdullah Almutairi, Esam I. Azhar, Christian Drosten, Simon J. Watson, Paul Kellam, Matthew Cotten, Alimuddin Zumla, Respiratory Tract Samples, Viral Load, and Genome Fraction Yield in Patients With Middle East Respiratory Syndrome The Journal of Infectious Diseases, Volume 210, Issue 10, 15 November 2014, Pages 1590–1594, https://doi.org/10.1093/infdis/jiu292

farcas

Farcas GA, Poutanen SM, Mazzulli T, Willey BM, Butany J, Asa SL, Faure P, Akhavan P, Low DE, Kain KC: Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus. J Infect Dis 2005, 191:193-197 https://doi.org/10.1086/426870

Covid-19 Symptoms depending on Infection Pathway

Streeck

Infection fatality rate of SARS-CoV2 in a super-spreading event in Germany Summarized on the Spread Analyses Page

Expression Locations of ACE2

timens

I Hamming, W Timens,MLC Bulthuis, AT Lely, GJ Navis and H van Goor Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis Journal of Pathology J Pathol 2004; 203: 631–637 Published online in Wiley InterScience https://doi.org/10.1002/path.1570

Jia 2005

Hong Peng Jia, Dwight C. Look, Lei Shi, Melissa Hickey, Lecia Pewe, Jason Netland, Michael Farzan, Christine Wohlford-Lenane, Stanley Perlman, Paul B. McCray ACE2 Receptor Expression and Severe Acute Respiratory Syndrome Coronavirus Infection Depend on Differentiation of Human Airway Epithelia
Jr Journal of Virology Nov 2005, 79 (23) 14614-14621; https://doi.org/10.1128/JVI.79.23.14614-14621.2005 Summary Jia 2005 on the coronavirus page.

li

Xu, H., Zhong, L., Deng, J., Peng, J., Dan, H., Zeng, X., Li, T., & Chen, Q. (2020). High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. International journal of oral science, 12(1), 8. https://doi.org/10.1038/s41368-020-0074-x

Disease Pattering for Influenza

Summary Bertram 2012

Bertram S, Heurich A, Lavender H, Gierer S, Danisch S, …, Soilleux,Poehlmann (2012) Influenza and SARS-Coronavirus Activating Proteases TMPRSS2 and HAT Are Expressed at Multiple Sites in Human Respiratory and Gastrointestinal Tracts. PLoS ONE 7(4): e35876. doi:10.1371/journal.pone.0035876

Findings

• Table 1 in the paper gives a concise summary of the availability of the receptors and proteases across the respiratory tract.
• “Here, we show that both HAT and TMPRSS2 are coexpressed with 2,6-linked sialic acids, the major receptor determinant of human influenza viruses, throughout the human respiratory tract. Similarly, coexpression of ACE2, the SARS-coronavirus receptor, and TMPRSS2 was frequently found in the upper and lower aerodigestive tract, with the exception of the vocal folds, epiglottis and trachea. Finally, activation of influenza virus was conserved between human, avian and porcine TMPRSS2, suggesting that this protease might activate influenza virus in reservoir-, intermediate- and human hosts.”

Appendix

ACE2 Receptor

ACE2 Receptor Detection

There are two common methods to measure tissue distribution of proteins:

• Antibody Staining

  Proteins on cell surfaces can be visualized by using marked antibodies. Several groups have analyzed tissues with ACE2 antibodies: Timens, McCray, soilleux, poehlmann

• Measure mRNA

  Measure ACE2 mRNA expression. Necessary condition for a cell to produce a protein. However not sufficient for ACE2 on apical cell surface [to confirm]. The mRNA expression across the human body is shown in Li et al.

Challenges for ACE2 Detection

[in work, verification needed] For serving as an entry point, ACE2 needs to be built into the cell membrane as a receptor i.e. being useable from the outside.

Since coronaviruses have a preference for apical tissue sites ACE2 should be expressed on the apical sites.

• Antibody staining alone can yield false positives if the cells are not properly cleaned and ACE2 is just attached to the cell without being built into the cell membrane.
• Measuring mRNA just detects if the cells produces ace2. But proteins produced by a cell can
  • stay in the cell e.g. in the cytoplasm or move into the nucleus
  • be released from the cell
  • being built into the cell membrane on the basal side or on the apical side as a receptor <= needed by coronaviruses.

Receptor detection rules:

• If both receptor detection methods yield true, this is very likely.
• Antibody staining is likely enough if the ‘receptor molecule’ cannot be attached on the outside of a cell or if it can be cleaned away.
• Measuring mRNA is enough if the ‘receptor’ is always exposed on the cell membrane if produced and thus not reside intracellular.

ACE2 Receptor Distribution

[incomplete and in rework] [recommended read is Bertram 2012 where ACE2 receptor distribution obtained from tissue staining is described] ACE2 is apically available

• in the lower respiratory tract
  • well-differentiated and ciliated airway epithelia (mcray05)
  • alveolar epithelial type 2 cells [to check/find citation].
• in the upper respiratory tract
  • the basal layer of the non-keratinised squamous epithelium of the nasal, oral mucosa and the nasopharynx expresses ACE2 Timens, Lau [in rework].
  • goblet cells [in work]

On the Origin

The origin of Sars-CoV-1 is unclear: Related viruses are found in bats and even more similar in civet cats. However seroprevalence of antibodies in civet cats suggest that Sars-CoV-1 is not endemic to civet cats and thus there was a jump to civet cats around the same time (2002) when Sars-CoV-1 jumped to humans.

The origin of Sars-CoV-2 is unknown. Considering its tropism, animal farming origin with frequent and even persistent infections of farmers is a possibility. Goats or sheep could be the hosts of the Sars-2 viruses, possibly even of Sars-like in general. That Sars-CoV-2 was discovered in a live-animal-market goes in line or a least is no contradiction with a farming origin: Rare severe cases in rural areas may not have rung the bells. However severe lung disease cases connected to a live-animal-market, could have triggered thorough investigations resulting in the discovery of Sars-CoV-2. The capable virology research facility in Wuhan possibly sped the discovery.

Virus discovery is not easy and requires the right settings. Some of the settings often need to be guessed since the virus in question are unknown. The human coronaviruses HKU1 and NL63 have been discovered only in 2004/5 despite both being endemic to human for a long time and virologists had the (theoretical) possibilities to discover coronaviruses since the 70’s. MERS got discovered in 2012 but likely human infections have occurred long before.

On this page (and for me) the originating i.e. the natural hosts are of relevance since they could inspire treatment methods: A hypothesis that SARS-like have a dual host life cycle in their natural habitat is discussed in Backtracing SARS-like.

The current Covid crisis is both risk and chance. It has to potential to split societies and the world. It is a chance to increase cooperations and sharing, our understanding of nature, transparency and fairness, to cooperate and to respect each other - all all.