Figure 1: Person to person transmission of SARS-CoV-2 mainly
depends upon air droplets and direct contact with infected person. After
the transmission the viral particles undergo six step viral replication
in human body such as 1) Viral entry through plasma membrane or
endosomes 2) translation of viral replicating machinery 3) replication
of viral particles 4) structural proteins translation 5) assembly of
virion and 6) release of the viruses. Furthermore, the figure also
explains the immune responses and conditions which develop after the
infection. There are three types of infections; asymptomatic, mild and
severe.
SARS-CoV-2 infection cycle starts from the entry of viral particle into
the host cell. SARS-CoV-2 can enter into host cell in two ways; either
through plasma membrane fusion or through endosomes (Hoffmann et al.,
2020). When the virions enter in to the endosomes, L cathepsin activates
the S protein. Although, the spike protein can also be activated by
cellular serine protease TMPRSS2 in close proximity to the ACE2
receptor, that starts with the fusion of viral membrane and the plasma
membrane (Hoffmann et al., 2020). Viral fusion entry less activates the
immune system therefore, more efficient for viral replication (Shirato
et al., 2018). The S proteins play a vital role in the attachment of
virion with the host cell membrane (Ramanathan et al., 2020). It
consists of two basic subunits S1 and S2. The S1 subunit consists on a
signal peptide (SP) which is proceeded through Receptor Binding domain
(RBD) and N-terminal domain (NTD), while S2 subunit consists on the I
and II heptad repeat (HR), cytoplasmic domain (CPD), Transmembrane
domain (TMD), and fusion peptide (FP) (Cai et al., 2020). Genome
encoding initiates after the entry into human cells (respiratory tract
cells) and facilitates the expression of genes (protein synthesis) which
run the adaptation of CoVs to their human host (Su et al., 2016).
1.2. Replication and translation of SAR-CoV-2 Machinery:
When SARS-CoV-2 enters the body, it releases its RNA into the host lung
cells, and polypeptides immediately undergo translation. Nonstructural
proteins (NPs), that have a very important function in viral RNA and
structural proteins’ synthesis, have a very critical role in virion
assembly formed by the viral genomic RNA encoding. Pp1a and pp1ab are
the first polypeptides that are translated to form functional NSPs as
helicase or RdRp (Shin, Jung, Kim, Baric, & Go, 2018).
1.3. Translation of viral structural proteins, virion assembly
and Release:
RdRp are very important enzymes that are responsible for the replication
of viral structural proteins of RNA. S1, S2, E and M are structural
proteins translated via ribosomes that are attached with endoplasmic
reticulum (ER) and expressed on its surface as preparation of virion
assembly. N proteins remain in cytoplasm and are assembled from genomic
RNA. They bound to the virion precursor which is then transported via
small vesicles from the ER through Golgi Apparatus to cell surface
(Zhong et al., 2003). Virions are then released from the infected cell
through exocytosis which then search for another host cell to infect.
Immune response:
Immune system shows response against COVID-19 into 2 distinct phases (Ⅰ,
Ⅱ). Phase Ⅰ immune response initiates during the incubation and
non-severe stage of SAR-CoV-2. Fully functional and specific adaptive
immune response is required to eliminate SAR-CoV-2 and to stop the
disease progression to severe stages. At this stage of disease,
anti-sera and IFN α treatments are important strategies for the
protective endogenous immune response. Host generally has good health
and appropriate immune genetic background that produce excellent
antiviral immunity (Shi et al., 2020). When the protective immune
response is failed to elicit the disease, the virus propagates to a
severe stage and triggers the phase Ⅱ immune response. Phase Ⅱ immune
response includes severe cytokines storms and pro-inflammation (Guo et
al., 2020). According to Lancet reports, the prime factor of causalities
with COVID-19 is the progression of acute respiratory distress syndrome
(ARDS) (Kalkeri, Goebel, & Sharma, 2020). One of the key mechanism of
ARDS is the massive release of cytokines named as cytokines storm which
leads to abandoned systemic inflammation due to the release of IFN- α,
IFN-g, IL-1b, IL-6, IL-12, IL-18, Il-33, TNF- α, and TGFb and many other
chemokines CCL2, CCL3, CCL5, CXCL8, and CXCL-10, etc. (Ahmed, Shah,
Rahim, Flores, & O’Linn, 2020). This lead to multi-organ failures like
kidney and lungs (Ahmed et al., 2020), while the immune system of aged
persons bear many age-related consequences that effect nearly each
component of immune system collectively termed as immune senescence
(Nikolich-Zugich et al., 2020). It changes the face themselves and
enhance the morbidity and mortality rate with infectious diseases
especially COVID-19 which affect both adaptive and innate immune system
as well as the cooperation of immune response itself in time and space
which work effectively in young adults but deteriorate with age.
Globally, cytokines signalling, peroxide production, nitric oxide and
phagocytic functions of neutrophils all are reduced in older people
(Nikolich-Žugich, 2018). The macrophages ability of phagocytoses also
become limited due to defective phosphorylation of activating enzymes to
limit and delay cytokines secretions (Desai, Grolleau‐Julius, & Yung,
2010). Age related changes disturb the functionality of dendritic cell
(DC, s), to encompass reduced uptake of antigen and diminish the
maturation, migration and formulation of co-stimulatory molecules and
necessary cytokines for T cells stimulations (Nikolich-Žugich, 2018).
Furthermore, adaptive immune system is also significantly affected by
age related factors. It diminishes both, B and T cells functions.
Activation of old B cells face serious issues in the initiation of a
vital E47 and AID transcription factor.
Improper induction of these important enzymes, in case of class
switching and somatic cell hyper-mutation, head to decrease avidity of
antibodies in aged patients (Nikolich-Žugich, 2018). T –cells are also
affected enormously by age related changes and the proliferation of
T-cells and expression of IL-2 is also reduced. CD4+TN cells in old humans, whereby, diminish T-cells receptors’ (TCR)
signalling and population increment were associated with age linked
destruction of miR-181, an important microRNA 53. MicroRNA commonly
suppresses the phosphatase that attenuate TCR signalling. T-helper cells
and downstream effector molecules like TNF, TNF-γ, granzyme B cells and
others are also reduced (Nikolich-Zugich et al., 2020). A brief
information is beyond this review scope, although, the aggregation of
these alterations leaves aged people particularly susceptible to
emerging infectious disease. This is, because, with advancing age, T and
B-cells production starts dropping and at the age of 40-50 years, only
10% of T-cells are left as compared to the children and youngsters.
This is the reason that why elderly people are more prone to infections
(Chinn, Blackburn, Manley, & Sempowski, 2012).
CURRENT TREATMENT STRATIGIES FOR COVID-19:
To date, there is no specific antiviral drug and vaccine recommended for
the treatment of COVID-19, however, UK and Germany are trailing their
vaccines against COVID-19. The only treatment available is oxygen
therapy which constitute the prime treatment intervention for patients
with serious respiratory infections. Moreover, among other therapeutic
strategies and a number of drugs, only a few have been used on patients
with SARS-CoV and MERS-CoV infections and a few are being tested
including remdisivir, baricitnib, hydroxychloroquine and the drugs used
against influenza, favipiravir, chloroquine and others being considered
(Chinn et al., 2012).
Wang et al. disclosed that chloroquine (anti-malarial drug) in
combination with remdesivir is highly effective against the COVID-19.,
because chloroquine results great in in-vitro impacts on the suppression
of uncoating of viruses. It does not allow a virus to uncoat and release
its genome. It also inhibits alteration of post-translational changes of
newly synthesized proteins, it also does suppression of glycosylation in
several viruses, including human immunodeficieny virus (HIV) (Wang et
al., 2020). The advantage of exploring such drugs is that there is
already a large number of information available about the bases of their
usage and safety in humans and it is important that despite the urgency,
the introduction of new therapies should not be pressed at the expense
of safety. Moreover, Chinese traditional medicines have gained wide
adoption, particularly in curing mild symptoms of COVID-19. A Chinese
patent medicine Lianhuaqingwen (LH), which is formed of 13 herbs has
played a positive role in the treatment of COVID-19 as it exerts broad
spectrum impact on the group of influenza viruses by restricting viral
propagation (Runfeng et al., 2020). Furthermore, immunotherapy by
applying IgG in combination with antiviral drugs can be applied to treat
and prevent COVID-19 and to make the immune response stronger against
this virus. The IgG may be applied to neutralize the virus causing
COVID-19 and the efficacy of IgG antibodies would be best if they were
isolated from patients recovered from COVID-19 (Jawhara, 2020).
A research which include four rhesus monkeys introduce that formulating
SARS-CoV-2 saved against future reoccurring of infections. When
scientists re-infected Ⅱ of the Ⅳ monkeys by this virus after 28 days of
initial infection, a total of 96 anal swabs and nasopharyngeal swabs
resulted negative (–ve) after the re-exposure of SARS-CoV-2. The
euthanasia and necropsy findings of Ⅰ of the Ⅱ monkeys confirmed these
results. These results suggested that immune response raised by Ⅱ
animals have saved them from future infection of SARS-CoV-2. Hoffmann et
al; studied, whether antibodies produced by patients who have been
previously diagnosed positive (+) for SARS would prevent SARS-CoV-2
entry into the cell. They also analysed that the antibodies against
SARS-CoV S protein limit how well in the in-vitro model virus with a
SARS-CoV-2 S protein could infect cells (Golchin, Seyedjafari, &
Ardeshirylajimi, 2020). They also saw similar findings with antibodies
against S proteins produced in rabbits. These findings showed that
neutralizing antibody responses formed against SARS-CoVs could offer
some safety against SARS-CoV-2 infection, which can be used for the
prevention of COVID-19 infection (Hofmann & Pöhlmann, 2004). Moreover,
the passive immunization with convalescent sera having (Ab)antibodies
from individuals who have recovered from COVID-19, could prevent
COVID-19 infection as argued by Casadevall and Pirofski (Golchin et al.,
2020). Some investigational treatments for COVID-19 are given in table
1.
To reduce the damage linked to COVID-19, global public health and
infection control programs are exigently needed to bound the world wide
transmission of virus. In COVID-19 victim’s travel history has great
significance for early discovery and isolation of SARS-CoV-2 pneumonia
cases. It is necessary to reduce person to person transmission in order
to limit secondary infections (Garami, 2020). Currently, prevention is
the only strategy that can limit spread of COVID-19 (Anderson,
Heesterbeek, Klinkenberg, & Hollingsworth, 2020).
Table 1: Investigational treatments of COVID-19