Publications by authors named "Jorge A Masso-Silva"

8 Publications

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Chronic E-Cigarette Aerosol Inhalation Alters the Immune State of the Lungs and Increases ACE2 Expression, Raising Concern for Altered Response and Susceptibility to SARS-CoV-2.

Front Physiol 2021 31;12:649604. Epub 2021 May 31.

Pulmonary Critical Care Section, VA San Diego Healthcare System, La Jolla, CA, United States.

Conventional smoking is known to both increase susceptibility to infection and drive inflammation within the lungs. Recently, smokers have been found to be at higher risk of developing severe forms of coronavirus disease 2019 (COVID-19). E-cigarette aerosol inhalation (vaping) has been associated with several inflammatory lung disorders, including the recent e-cigarette or vaping product use-associated lung injury (EVALI) epidemic, and recent studies have suggested that vaping alters host susceptibility to pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To assess the impact of vaping on lung inflammatory pathways, including the angiotensin-converting enzyme 2 (ACE2) receptor known to be involved in SARS-CoV-2 infection, mice were exposed to e-cigarette aerosols for 60 min daily for 1-6 months and underwent gene expression analysis. Hierarchical clustering revealed extensive gene expression changes occurred in the lungs of both inbred C57BL/6 mice and outbred CD1 mice, with 2,933 gene expression changes in C57BL/6 mice, and 2,818 gene expression changes in CD1 mice (>abs 1.25-fold change). Particularly, large reductions in IgA and CD4 were identified, indicating impairment of host responses to pathogens reductions in immunoglobulins and CD4 T cells. CD177, facmr, tlr9, fcgr1, and ccr2 were also reduced, consistent with diminished host defenses decreased neutrophils and/or monocytes in the lungs. Gene set enrichment (GSE) plots demonstrated upregulation of gene expression related to cell activation specifically in neutrophils. As neutrophils are a potential driver of acute lung injury in COVID-19, increased neutrophil activation in the lungs suggests that vapers are at higher risk of developing more severe forms of COVID-19. The receptor through which SARS-CoV-2 infects host cells, ACE2, was found to have moderate upregulation in mice exposed to unflavored vape pens, and further upregulation (six-fold) with JUUL mint aerosol exposure. No changes were found in mice exposed to unflavored Mod device-generated aerosols. These findings suggest that specific vaping devices and components of e-liquids have an effect on ACE2 expression, thus potentially increasing susceptibility to SARS-CoV-2. In addition, exposure to e-cigarette aerosols both with and without nicotine led to alterations in eicosanoid lipid profiles within the BAL. These data demonstrate that chronic, daily inhalation of e-cigarette aerosols fundamentally alters the inflammatory and immune state of the lungs. Thus, e-cigarette vapers may be at higher risk of developing infections and inflammatory disorders of the lungs.
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http://dx.doi.org/10.3389/fphys.2021.649604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194307PMC
May 2021

Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: a case series and review of the literature.

Clin Infect Dis 2021 May 14. Epub 2021 May 14.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.

Background: Increased inflammation has been well defined in COVID-19, while definitive pathways driving severe forms of this disease remain uncertain. Neutrophils are known to contribute to immunopathology in infections, inflammatory diseases and acute respiratory distress syndrome (ARDS), a primary cause of morbidity and mortality in COVID-19. Changes in neutrophil function in COVID-19 may give insight into disease pathogenesis and identify therapeutic targets.

Methods: Blood was obtained serially from critically ill COVID-19 patients for eleven days. Neutrophil extracellular trap formation (NETosis), oxidative burst, phagocytosis and cytokine levels were assessed. Lung tissue was obtained immediately post-mortem for immunostaining. Pubmed searches for neutrophils, lung and COVID-19 yielded ten peer-reviewed research articles in English.

Results: Elevations in neutrophil-associated cytokines IL-8 and IL-6, and general inflammatory cytokines IP-10, GM-CSF, IL-1b, IL-10 and TNF, were identified both at first measurement and across hospitalization (p<0.0001). COVID neutrophils had exaggerated oxidative burst (p<0.0001), NETosis (p<0.0001) and phagocytosis (p<0.0001) relative to controls. Increased NETosis correlated with leukocytosis and neutrophilia, and neutrophils and NETs were identified within airways and alveoli in lung parenchyma of 40% of SARS-CoV-2 infected lungs available for examination (2 out of 5). While elevations in IL-8 and ANC correlated with disease severity, plasma IL-8 levels alone correlated with death.

Conclusions: Literature to date demonstrates compelling evidence of increased neutrophils in the circulation and lungs of COVID-19 patients. importantly, neutrophil quantity and activation correlates with severity of disease. Similarly, our data shows that circulating neutrophils in COVID-19 exhibit an activated phenotype with enhanced NETosis and oxidative burst.
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http://dx.doi.org/10.1093/cid/ciab437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241438PMC
May 2021

Cigarette Smoke Exposure Promotes Virulence of Pseudomonas aeruginosa and Induces Resistance to Neutrophil Killing.

Infect Immun 2020 10 19;88(11). Epub 2020 Oct 19.

Pulmonary and Critical Care Section, VA San Diego Healthcare System, La Jolla, California, USA

It is widely known that cigarette smoke damages host defenses and increases susceptibility to bacterial infections. , a Gram-negative bacterium that commonly colonizes the airways of smokers and patients with chronic lung disease, can cause pneumonia and sepsis and can trigger exacerbations of lung diseases. colonizing airways is consistently exposed to inhaled cigarette smoke. Here, we investigated whether cigarette smoke alters the ability of this clinically significant microbe to bypass host defenses and cause invasive disease. We found that cigarette smoke extract (CSE) exposure enhances resistance to human neutrophil killing, but this increase in pathogenicity was not due to resistance to neutrophil extracellular traps. Instead, exposed to CSE (CSE-PSA) had increased resistance to oxidative stress, which correlated with increased expression of , a gene essential for defense against oxidative stress. In addition, exposure to CSE induced enhanced biofilm formation and resistance to the antibiotic levofloxacin. Finally, CSE-PSA had increased virulence in a model of pneumonia, with 0% of mice infected with CSE-PSA alive at day 6, while 28% of controls survived. Altogether, these data show that cigarette smoke alters the phenotype of , increasing virulence and making it less susceptible to killing by neutrophils and more capable of causing invasive disease. These findings provide further explanation of the refractory nature of respiratory illnesses in smokers and highlight cigarette smoking as a potential driver of virulence in this important airway pathogen.
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http://dx.doi.org/10.1128/IAI.00527-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573448PMC
October 2020

The Evolving Landscape of e-Cigarettes: A Systematic Review of Recent Evidence.

Chest 2020 05 30;157(5):1362-1390. Epub 2020 Jan 30.

School of Medicine, University of Adelaide, Adelaide, SA, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia. Electronic address:

Smoking continues to be a burden to economies and health-care systems across the world. One proposed solution to the problem has been e-cigarettes; however, because they are a relatively new product in the market, little is known about their potential health impacts. Furthermore, e-cigarettes continue to evolve at a rapid rate, making it necessary to regularly review and summarize available studies. Although e-cigarettes are marketed as a smoking cessation tool by some manufacturers, the reality is that many nonsmokers, including youth, are using them. This review focuses on two major demographic groups (smokers and nonsmokers) and evaluates the most recent data (early 2017 to mid 2019) regarding the potential health effects of e-cigarettes. We assessed peer-reviewed studies on the health impacts of e-cigarettes, with a particular focus on common questions asked by policy makers, clinicians, and scientists: (1) What are the effects of e-cigarettes compared with air/not smoking?; (2) Is there any direct evidence of harm or benefit to humans?; (3) Is there a risk from secondhand exposure?; (4) What are the risks and/or benefits of e-cigarettes compared with tobacco cigarette use?; (5) Are there risks or benefits to specific populations (eg, people with COPD or asthma, pregnant women [and their offspring])?; (6) What are the effects of flavoring chemicals?; (7) What are the effects of including nicotine in e-liquids?; (8) How often is nicotine concentration labeling incorrect?; and (9) What are the risks when e-cigarettes explode?
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http://dx.doi.org/10.1016/j.chest.2019.12.042DOI Listing
May 2020

A Heat-Killed Mutant Strain Induces Host Protection against Multiple Invasive Mycoses in a Murine Vaccine Model.

mBio 2019 11 26;10(6). Epub 2019 Nov 26.

Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA

is a fungal pathogen that infects the lungs and then often disseminates to the central nervous system, causing meningitis. How is able to suppress host immunity and escape the antifungal activity of macrophages remains incompletely understood. We reported that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase, promotes virulence by regulating host- interactions. Our recent studies demonstrated that the Δ mutant elicited superior protective Th1 host immunity in the lungs and that the enhanced immunogenicity of heat-killed Δ yeast cells can be harnessed to confer protection against a subsequent infection with the virulent parental strain. We therefore examined the use of heat-killed Δ cells in several vaccination strategies. Interestingly, the vaccine protection remains effective even in mice depleted of CD4 T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that vaccinating mice with heat-killed Δ induces significant cross-protection against challenge with diverse invasive fungal pathogens, including , , and , as well as partial protection against Thus, our data suggest that the heat-killed strain has the potential to be a suitable vaccine candidate against cryptococcosis and other invasive fungal infections in both immunocompetent and immunocompromised populations. Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in , elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4 T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations.
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http://dx.doi.org/10.1128/mBio.02145-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879717PMC
November 2019

Host response to pulmonary fungal infections: A highlight on cell-driven immunity to species and .

Curr Pharmacol Rep 2017 Dec 14;3(6):335-345. Epub 2017 Oct 14.

Center for Immunity and Inflammation New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA.

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http://dx.doi.org/10.1007/s40495-017-0111-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804991PMC
December 2017

Activity of potent and selective host defense peptide mimetics in mouse models of oral candidiasis.

Antimicrob Agents Chemother 2014 Jul 21;58(7):3820-7. Epub 2014 Apr 21.

Department of Oral Biology, Rutgers School of Dental Medicine, Newark, New Jersey, USA

There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis.
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http://dx.doi.org/10.1128/AAC.02649-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068575PMC
July 2014

Antimicrobial peptides from fish.

Pharmaceuticals (Basel) 2014 Mar 3;7(3):265-310. Epub 2014 Mar 3.

Department of Oral Biology, University of Florida, Box 100424, Gainesville, FL 32610, USA.

Antimicrobial peptides (AMPs) are found widely distributed through Nature, and participate in the innate host defense of each species. Fish are a great source of these peptides, as they express all of the major classes of AMPs, including defensins, cathelicidins, hepcidins, histone-derived peptides, and a fish-specific class of the cecropin family, called piscidins. As with other species, the fish peptides exhibit broad-spectrum antimicrobial activity, killing both fish and human pathogens. They are also immunomodulatory, and their genes are highly responsive to microbes and innate immuno-stimulatory molecules. Recent research has demonstrated that some of the unique properties of fish peptides, including their ability to act even in very high salt concentrations, make them good potential targets for development as therapeutic antimicrobials. Further, the stimulation of their gene expression by exogenous factors could be useful in preventing pathogenic microbes in aquaculture.
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http://dx.doi.org/10.3390/ph7030265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978493PMC
March 2014
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