ABSTRACT
The role of steroid hormones against infectious diseases has been extensively studied. From immunomodulatory action to direct inhibition of microorganism growth, hormones D3 (VD3) and 17beta-estradiol (E2), and the genetic pathways modulated by them, are key targets for a better understanding pathogenesis of infectious respiratory diseases (IRD) such as tuberculosis (TB) and the coronavirus disease-19 (COVID-19). Currently, the world faces two major public health problems, the outbreak of COVID-19, accounting for more than 6 million so far, and TB, more than 1 million deaths per year. Both, although resulting from different pathogens, the Mtb and the SARS-CoV-2, respectively, are considered serious and epidemic. TB and COVID-19 present similar infection rates between men and women, however the number of complications and deaths resulting from the two infections is higher in men when compared to women in childbearing age, which may indicate a role of the sex hormone E2 in the context of these diseases. E2 and VD3 act upon key gene pathways as important immunomodulatory players and supporting molecules in IRDs. This review summarizes the main roles of these hormones (VD3 and E2) in modulating immune and inflammatory responses and their relationship with TB and COVID-19.Copyright © Sociedade Brasileira de Genetica.
ABSTRACT
RATIONALE: INNA-051 is a Toll-like receptor (TLR) 2/6 agonist delivered via intranasal spray, being developed for treatment of respiratory viral diseases. Pre-clinical studies demonstrate that INNA-051 and analogues are effective against a variety of respiratory viruses including SARS-CoV- 2, influenza, and rhinovirus. INNA-051 induces a tissue-localized innate immune response with cytokine expression and infiltration of innate immune cells into the nasal epithelium that play a key role in viral clearance. The primary objective of this study (ACTRN12621000607875p) was evaluation of safety and tolerability in healthy adults. METHODS: This was a randomized, doubleblind, placebo-controlled, Phase 1 study of single and multiple ascending INNA-051 intranasal doses, with the total dose split evenly across both nostrils. Sixty-four participants ages 18-55 were enrolled, with 5 cohorts (6 active:2 placebo/cohort) receiving single doses of 20μg, 60μg, 150μg, 300μg, or 600μg, and 3 cohorts (6 active:2 placebo/cohort) receiving 4 total doses of 60μg, 150μg, and 300μg administered every third day. Assessments included adverse events, clinical laboratories, peak inspiratory nasal flow (PINF), and peak expiratory flow (PEF).RESULTS: Sixtyfour participants (36 males:28 females) ages 19-55 years were enrolled. Preliminary blinded results demonstrate that INNA-051 was well tolerated across all single and multiple dose cohorts. Adverse events were predominantly mild, limited to the nasopharynx, and resolved within 24-48 hours. Across single dose cohorts, the most frequent events were nasal congestion/blockage (n=20), nasal erythema/inflammation (n=19), rhinorrhea (n=13) and headache (n=11). Except for the 20-μg cohort with only 2 reports of rhinorrhea, all other single dose cohorts had a similar incidence of the other adverse events with no obvious dose relationship. Across all 3 multiple dose cohorts, nasal erythema/inflammation (n=42) was most frequently reported, followed by nasal congestion/blockage (n=26), rhinorrhea (n=9), and headache (n=9), with no dose-dependent relationship. No participants withdrew from the study due to adverse events. There were no clinically significant changes in clinical chemistry and hematology laboratories across all single and multiple dose cohorts. No consistent decrease in post-dose PNIF assessments were observed, and there were no changes in PEF assessments to suggest lower respiratory tract airway response to intranasal INNA- 051.CONCLUSIONS: Intranasal INNA-051 was well tolerated up to single doses of 600μg and multiple doses of 300μg. Mild, self-limited nasal adverse events as described are possible indicators of tissue-localized innate immune response by INNA-051. Investigation of cytokine levels and gene expression of the intranasal epithelium are needed to specifically determine TLR2/6 engagement by INNA-051.
ABSTRACT
SARS-CoV-2 is a coronavirus that infects epithelial cells in the naso- and oropharynx before infecting epithelial cells of the lower airways and alveoli and in severe COVID-19 spreading systemically and inducing a systemic inflammatory response. SARS-CoV-2 is spread mainly by virus particles in droplets and aerosols. This suggests that inhaled therapies may be useful in the treatment of early COVID-19 disease before severe respiratory systemic features develop and potentially in reducing transmission of the virus in the community. To be effective any inhaled therapy must be rapidly acting to prevent viral replication in respiratory epithelial cells to prevent the disease spreading down the respiratory tract and into the systemic circulation. It also needs to be safe and available for early prescription in order to prevent severe disease and hospitalisation. The development of inhaled therapies for COVID-19 may involved repurposing of existing inhaled therapies or developing inhaled formulations of new drugs with antiviral effects. Patients with asthma and COPD were reported to be less likely to be hospitalised with SARS-CoV-2 infection despite the concern that this coronavirus would have severe consequences for these patients as coronaviruses are known to trigger severe exacerbations. One possibility was that this may be due to the widespread treatment with inhaled corticosteroids (ICS), which are known to suppress ACE2 and TMPRSS2 on epithelial cells that are key entry receptors for the virus and also reduce virus replication in vitro. A community based open label parallel group phase 2 study of the ICS budesonide (800 lg bid until recovery) in people with early symptoms (within 7 days of onset) of COVID-19 and confirmed by PCR testing (STOIC) showed that only 1/69 people in the ICS group developed severe disease compared with 10/70 in the usual care group.1 Clinical recovery was also shorter in the ICS group. This finding was confirmed in an open label study of inhaled budesonide in individuals over the age of 65 years at risk from severe COVID-19 (PRINCIPLE), which showed a reduction in time to recovery and a trend towards reduced hospitalisation and death.2 Several other trials, including double-blind studies, of ICS in early COVID-19 are currently underway with different corticosteroids, including ciclesonide, which appears to be the most effective against SARS-CoV-2 in vitro.3 However, a recent double-blind study of nasal and inhaled ciclesonide failed to show any benefit in early COVID-19, although the population was mainly young adults who have a low risk of disease progression.4 The mechanism of action of ICS in COVID- 19 has not yet been established, but may involve reduced viral entry due to suppression of ACE2 and TMPRSS2 in airway epithelial cells, reduced viral proliferation or reduced inflammatory mediators secreted by airway epithelial cells that may promote viral spreading. Interferon b1 is currently approve for treating multiple sclerosis. Nebulised IFN-b1a (SNG001) gave a greater degree of clinical improvement in hospitalised COVID-19 patients and a reduction on symptoms (mainly dyspnoea) compared to with placebo and was well tolerated.5 However, studies in early disease are underway but have not yet been reported, although there are logistical problems in the need for a nebuliser to deliver the drug. Inhaled PUL-42 is a combination of a TLR2/6 and a TLR9 inhibitors which is effective in a single inhaled dose against SARS-CoV and MERS-CoV infection in mice and reduces the lung viral load.6 This drug is now in clinical trials for COVID-19. Other inhaled drugs, including antivirals such as remdesivir and niclosamide, are also in development.