AUTHOR: SEOK WOO YANG, MD & PhD.
CONTACT: E.mail; soplab@outlook.kr
DATE: 2020.03.19
CONTENT:
Conventional coronavirus is known as an ss(single-stranded) RNA virus. Its incubation period is 2 ~ 5 days, whereas novel coronavirus is 4 ~ 14 days and SARS one is 2 ~ 7 days.
As supportive evidence of the incubation period of novel coronavirus longer than that of SARS coronavirus, there was a report three persons recovered from COVID-19 still had positive RT-PCR results for novel coronaviruses, even without symptoms and contagion into nearby family members.[1]
Its clinical implication has not been solved.
Despite novel coronaviruses are similar to SARS ones, why is the incubation period of novel coronaviruses longer than SARS ones?
What are the factors to explain the above phenomena?
In SARS, viral shedding is the nonlytic release of the vast majority of mature virions into the extracellular space via the Golgi apparatus from the ER.[2]. If novel coronavirus behaves in this way, the incubation period may be similar to that of SARS coronavirus.
If so, there must be the other pathway for viral shedding and replication to be continued except for the extracellular space, namely the intracellular space.
Which compartment of the intracellular space is probably suitable for viral shedding and replication?
The author supposes that the isolated hidden place for introverted viral shedding into the cell may be an intranuclear space, for the vast majority of viral release happens on the extracellular cytoplasmic border, as aforementioned.
The author infers the answer from the point that the main target cell organelle by novel coronavirus is endoplasmic-reticulum(ER).
Among four main proteins in coronaviruses, N protein forms a complex by binding to genomic RNA and M protein triggers the formation of interacting virions in this endoplasmic reticulum-Golgi apparatus intermediate compartment(ERGIC) with this complex.[3][4]
The characteristic electron microscopic findings of the alveolar epithelial cells in SARS cases are markedly dilated rough endoplasmic reticulum(RER) and smooth endoplasmic reticulum(SER).[5]
Uniquely, there was a comment on the membranous inclusion bodies in some nuclei.[5]
Considering the genetic & electron microscopic similarity of novel coronavirus to SARS coronavirus, the chance for nuclear inclusions to occur is high.
About the structure of nuclear inclusions, the reference journal did not include the related figure, and we can not clearly describe the electron microscopic feature to explain viral shedding into the intra-nuclear space.
Instead, the electron microscopic finding of nuclear inclusions in the cells may be an alternative tool to explain why nuclear inclusions in novel coronaviral infected cells can be a hidden reservoir for persistent viral replication.
About the detailed structure of nuclear inclusion, that in pituitary adenoma may be appropriate for a comparable explanation.
The nuclear inclusion in pituitary adenoma is composed of the ER-rich cytoplasm within the cell nucleus.
Yang et al(2003) analyzed the genesis of nuclear inclusion as the result of intracytoplasmic invagination into the nucleus. [6]
A part of the outline of the nuclear inclusion is composed of a double-layered membrane at the locus between the nucleus and the cytoplasm. Its origin can not be proved to be from whether ER or nuclear membrane.
The point is that nuclear inclusion includes ER-rich cytoplasmic components, which is continuous with the ER on the cytoplasmic side.
The author thinks that this nuclear inclusion with ER-rich cytoplasmic component can be a reservoir for persistent viral replication even during viral release into the extracellular space and cell division.
Despite the detrimental cytolytic cytotoxicity in COVID-19 cases, the presence of the long incubation period of novel coronaviruses can be explained by this hypothesis.
Hence, further research for novel coronaviruses should be performed to investigate the presence of nuclear inclusions in COVID-19 cases.
P.S.
If nuclear inclusions in COVID-19 cases will be found, please correspond to me about the next step for therapeutic strategy.
REFERENCE:
[1] Lan L, Xu D, Ye G, et al. Positive RT-PCR Test Results in Patients Recovered From COVID-19. JAMA. Published online February 27, 2020.
[2] Denison MR. CORONAVIRUS RESEARCH: KEYS TO DIAGNOSIS, TREATMENT, AND PREVENTION OF SARS. In: Institute of Medicine (US) Forum on Microbial Threats; Knobler S, Mahmoud A, Lemon S, et al., editors. Learning from SARS: Preparing for the Next Disease Outbreak: Workshop Summary. Washington (DC): National Academies Press (US); 2004.
[3] de Haan CA, Masters PS, Lili Kuo, Harry Vennema, Peter JM, Rottier. Coronavirus particle assembly: primary structure requirements of the membrane protein. J Virol. 1998; 72: 6838-6850.
[4] Escors D, Ortego J, Enjuanes L. The membrane M protein of the transmissible gastroenteritis coronavirus binds to the internal core through the carboxy-terminus. Adv Exp Med Biol. 2001; 494: 589-593.
[5] Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, Cai J, Li X, Kang W, Weng D, Lu Y, Wu D, He L, Yao K. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol. 2003 Jul;200(3):282-9.(PDF free download)
[6] Yang SW, Yang KM, Kang Hy, Kim TS. Intranuclear cytoplasmic pseudoinclusions in pituitary adenomas. Yonsei Med J. 2003 Oct 30;44(5):816-20.(PDF free download)