Infectious Disease Aerobiology and the Communicability of Airborne Disease
Research in the Division has focused on the study of respiratory-transmitted disease agents, with the long term goal of gaining a better understanding of the constellation of variables that are important to airborne infection. Over the last several years, through targeted scientific inquiry, we have dedicated our efforts to deciphering the factors essential to the initiation, transport, and primary infection through the aerosol route of exposure. Utilizing the tools and scientific resources unique to this line of investigation, we have harnessed laboratory-based engineered configurations for determining microbial efficiencies of high consequence pathogens when in aerosol. For example, studies have led to discoveries about the unexpected long term survival of Monkeypox virus, a known human respiratory pathogen, when in aerosol form. Using this unique aerosol generation and sampling system, collectively housed in our high biocontainment (BSL-3) laboratories, we have been able to perform aerosol survivability studies with bacterial agents as well. Building upon basic approaches to better understand the aerosol ecology of infectious agents relevant to human disease, we are also heavily invested in the in-depth study of the modeling disease using advanced animal species, including the nonhuman primate, using experimental aerosols as our modality of infection. The application of our work in aerosol biology of infectious agents, including our extensive efficiency studies performed with a number of infectious agents, is leveraged in ongoing animal trials. Using this comprehensive approach has provided significant traction towards reaching our long term research goal, and has richly contributed to the ongoing development of a better understanding of the complexities associated with the study of airborne infection in man.
Aerosol Ecology & Transmission of Infectious Disease
Very little is known about the temporal development of infectious bioaerosol generation in infectious hosts as well as the risk presented from aerosol particle transport from a contagious individual in the context of disease induction. Our research attempts to study these phenomena experimentally, using devices and laboratory apparatus within a high containment environment that supports these activities in a safe manner.
There is a known particle size distribution associated with impacting the most susceptible region of the respiratory system, and as such is of the most intensively studied. The difficulty with focusing only upon the ‘respirable’ fraction of any distribution containing infectious particles is that the human condition, in stark contrast, dictates that aerosols of a highly heterogeneous distribution are generated in infectious individuals considered contagious. The effect of particle size upon the relative viability of the pathogenic organism is highly variable and may be dependent upon the generator and subsequent transport. In addition, there are other variables, such as genetic composition, and strain-specific modification, that may also be determinative of survival in aerosol. Collectively, this is an exceedingly difficult problem to investigate in a laboratory setting.
As an exemplar of our research approach to defining microbial ecology of aerosolized pathogenic agents, we investigated influenza viruses to better understand factors important in to aerosol survival using many of the scientific tools available in the aerobiology laboratories. We determined that that strain-specific composition, and subsequent morphological differences between H1N1 (swine mutant) and H2N3 (seasonal variant) in part, is determinative of the efficiency of each of these viruses when in aerosol. The study of viral particles subsequent to aerosol generation and capture by aerosol sampling showed that a filamentous virion common to the H1N1 strain, in part, was much more susceptible to the rigors of the aerosol environment, and thus is less likely to maintain a form consistent with cellular entry, replication, and ultimately the induction of infection.
Animal Models of Aerosol Infection
Many of the high consequence respiratory human pathogens cannot be studied clinically nor are susceptible populations available to monitor because of the present-day episodic (or absence) incidence of disease. Research in our Division is focused on using animal species, with emphasis on the nonhuman primate, to model these diseases of interest. We leverage our knowledge about the aerosol characteristics of infectious agents as a cornerstone for experimental infection in many of these studies. Many of the agents that are of interest, such as ricin toxin, have no human clinical data from which to reference because there has never been a poisoning via inhalation with this biotoxin. Yet ricin is considered a biological threat agent of concern and thus there is a need for preventive or palliative measures in the event of a human exposure, ultimately necessitating the development of an animal model of (aerosol) intoxication. As such, research in our Division included an extensive investigation of the pathophysiology of aerosolized ricin exposure in the rhesus macaque, using our specifically engineered aerosol exposure delivery system within high containment. We showed that intoxication by this modality is exceedingly acute, per weight dose is similar to rodent species, and effects such as vascular leak induction occurs much earlier subsequent to exposure than originally envisioned. Also of interest in these studies was the previously unidentified cell migrations, specifically interstitial macrophages, into the lung parenchyma, and the associated architectural changes including extensive fibrosis noted in animals receiving sublethal aerosol doses of the toxin. This disease model subsequently was of intense interest to a number of collaborative groups seeking to evaluate candidate vaccines and therapeutics for prevention of the effects of ricin toxin.
Vaccine and Therapeutics Evaluation using Advanced Aerosol Infection Models
Development of advanced animal models that capture critical aspects of the human syndrome of disease has been a major focus of the Division for a number of years. The nonhuman primate represents the essential link between understanding human disease and development of measures to combat effects from infection. This relationship is most important for the study of high consequence human pathogens were little to no annual incidence of human disease exists nor does the epidemiology of these diseases support advanced evaluation and development of medical products. Accordingly, many of the animal models that incorporate aerosol as a modality of exposure have been used in the ongoing Divisional research for the evaluation of medical products.
A major effort involving the development of viable vaccines for the pathogenic alphaviruses – Eastern equine encephalitis, Western equine encephalitis, and Venezuelan equine encephalitis, and Chikungunya virus – was undertaken over the last several years. Individualized disease models for each virus were developed specifically to support each vaccine product due to differences in disease outcome and lack of cross protective capacity of the vaccines under development. Vaccine products with competing platforms (virally-vectored v. VLP) were evaluated using the nonhuman primate models that were developed as a consequence of this research effort. The disease models proved robust and durable for these purposes, and paired with immunogenicity, efficacy was achieved against all of the pathogenic viruses listed within this family.
The development and utilization of nonhuman primate models of alphaviral disease are one of a number of ongoing efforts that comprise the research in this area within our Division. We have leveraged many aspects of infectious disease aerobiology that although initially appearing disparate in focus, complements programmatically many of the research applications.
