Biographical Sketch

Nick Cianciotto received his BS degree in biological sciences from the University of California, Irvine, and his PhD degree in microbiology from the University of Washington. Following post-doctoral training at the University of Michigan, Dr. Cianciotto joined Northwestern as an assistant professor of microbiology-immunology in 1990. 

Research Description

Molecular pathogenesis of Legionella pneumophila, the bacterial agent of Legionnaires' disease; molecular and cellular bases of intracellular infection of human macrophages by bacterial pathogens; identification and characterization of bacterial genes and gene products that promote virulence; analysis of bacterial iron acquisition, adherence to host cells, secretion of toxins and other virulence factors, and antibiotic resistance.

Research Abstract

Legionella pneumophila, the agent of Legionnaires' disease, is a classic environmental, opportunistic pathogen. Strains of this bacterium are widespread within aquatic environments throughout the world. Due to its broad distribution within natural waters, L. pneumophila also exists within many man-made aquatic environments; recent surveys indicate that it is present in 60% of large buildings, including hospitals and hotels. The legionellae can infect humans following the inhalation of contaminated aerosols generated by air-conditioners, fountains, showers, humidifiers, whirlpools, and other devices. The ubiquity of L. pneumophila and the widespread use of aerosol-generating devices ensure that many individuals are exposed to the Legionnaires' disease bacterium. In the lower respiratory tract, L. pneumophila invades and proliferates to high numbers within alveolar macrophages and can, if unchecked, result in fatal pneumonia. The more serious forms of legionellosis are restricted to immunocompromised individuals, including transplant patients, the elderly, smokers, and alcoholics. The Legionella organism is a significant cause of both community-acquired and hospital-acquired pneumonia, accounting for an estimated 1-30 percent of cases. Current surveys indicate more than 25,000 cases of Legionnaires' disease occur per year in the US. Increases in the numbers of immunocompromised and elderly individuals signal that opportunistic pathogens, such as L. pneumophila, will continue as health problems. The advent of legionellosis as a clinical entity clearly illustrates how changes in our environment (in this case, the widespread use of aerosol generators) can expose us to potentially harmful microbes.

The aim of our research is to characterize the bacterial genes and gene products that promote the occurrence of Legionnaires' disease. In a broad sense, legionellosis is the consequence of a bacterium's capacity to flourish within both man-made water systems and the human lung. On the one hand, the aquatic distribution of L. pneumophila is a result of the bacterium's ability to replicate extracellularly in multi-organismal biofilms as well as intracellularly within amoebae and ciliates. On the other hand, the intrapulmonary spread of the legionellae is facilitated by both the infection of alveolar macrophages and the elaboration of toxins and degradative enzymes. It is widely believed that the ability of L. pneumophila to parasitize macrophages is derived from its "prior" adaptation to intracellular growth within aquatic protozoans. Bacterial persistence in the aquatic and mammalian environments is a complex, multifactorial process. However, one bacterial trait that is uniformly critical to survival and multiplication is the capacity to adhere to animate and/or inanimate surfaces.

Recent work in our laboratory has identified two potential adherence systems in L. pneumophila. The first nvolves a set of genes that produce hairlike-projections known as type IV pili or fimbriae. The second involves a gene encoding a large, afimbrial outer membrane protein. Current research is defining the precise roles of these adhesions in bacterial attachment to macrophages, alveolar epithelia, amoebae, and biofilms. A second bacterial trait that is required for pathogenesis is the secretion of proteins that damage host tissue, subvert host defenses, or promote nutrient assimilation. We have discovered a Legionella secretion apparatus that is absolutely critical for intracellular infection, and current efforts are aimed at defining the regulation of this system, its secreted products, and its precise intracellular function. A third characteristic of L. pneumophila, as well as any pathogen, is the capacity to scavenge iron from host chelators. Using new schemes for mutagenesis, we have isolated mutants that are defective for both iron uptake and macrophage infection. Ongoing analysis of these strains is uncovering the effectors of intracellular iron assimilation. In addition, we have identified the iron-responsive Fur protein as a transcriptional regulator of L. pneumophila virulence. The characterization of the Fur regulon represents an alternate approach toward elucidating iron-scavenging activities. A final bacterial trait that can contribute to the prevalence of an infectious disease is antibiotic resistance. While studying Legionella virulence, we have discovered several antibiotic resistance genes. Most interestingly, one of these Legionella genes encodes a novel antibiotic-inactivating enzyme.

In addition to bacterial attributes, host factors play a major role in determining the outcome of an infection; as noted above, immunocompromised individuals are at greater risk for Legionnaires' disease. As one approach toward understanding host susceptibility, our laboratory staff members in collaboration with Dr. Carl Waltenbaugh in our department are determining how alcohol consumption facilitates infection by L. pneumophila and other intracellular parasites. In conclusion, our laboratory staff employs a multi-faceted approach toward understanding the pathogenesis and natural history of Legionnaires' disease, with the hope that basic insights will lead to new methods of disease prevention, diagnosis, or treatment.

Recent Publications: 
(Click on icons at left to link with abstract NLM)

*Complete list of Dr. Ciancitto's publications on Pubmed website