Question

Stages of pathogenesis including virulence factors involved in pathogenesis for Legionnaires Disease

1. Describe how the pathogen is exposed to the host, this should at least include:
   a. the portal of entry
   b. the median infectious dose and lethal infectious dose. If this cannot be found, please say so.

2. Describe how the pathogen adheres to the host, this should at least include: a. the adhesin virulence factor(s) of the pathogen
   b. the host molecule(s) to which the adhesin(s) interact

3. Describe how the pathogen invades the host's cells/tissues, this should at least include a. the virulence factor(s) used to enter the cell or tissue
   b. a description of the pathogen invasion

4. Describe how the pathogen infects the host's cells/tissues, this should at least include
   a. the manifestation of the infection (see Week 13, How Pathogens Cause Disease, Outcome 7) b. the virulence factor(s) not yet mentioned that lead to the disease state

i. virulence factor(s) for survival in the host and/or immune evasion would go here

c. a description of the pathogen infection
i. for bacteria, fungi or protozoans this may include how the bacteria survives in the host

ii. for fungi, protozoans, or helminths this may include the life cycle of the organism iii. for viruses this must include the specific viral replication cycle

5. Describe how the pathogen transmits to a new host, this should at least include: a. the portal(s) of exit (if applicable)

Answer 1

How the pathogen is exposed to the host

Legionella pneumophila is a ubiquitous organism present in environment.But they rarely cause disease. Several factors should occur simultaneously for disease to occur.They are presence of virulent organism in the environment, the means of transmission such as aerosolisation,the environmental conditions suitable for survival of organism and inhalation of infective dose of the organism by a susceptible host.The portal of entry is respiratory tract.It enters by inhalation or micro aspiration into the lungs.The inoculum for causing disease is unknown. However in guinea pigs an inoculum of 10-100,1000,10000 bacteria cause asymptomatic infection, disease and death respectively

How the pathogen adhere to the host

Lcl is an adhesin expressed by Legionella pneumophila .It is a heparin binding protein. This binds to the sulfated glycosaminoglycan molecules in the extracellular matrix of host.Also type 4 pili modestly promote attachment to the macrophages and epithelial cells.

How the pathogen invade the host cell

Flagella helps in invasion independent of adhesion.Other virulence factors that are involved in invasion of alveolar macrophages and other host cells are the outer membrane protein porin and Mip protein, a surface exposed peptidyl prolyl isomerase. The organism enters the host cell by a mechanism called coiling phagocytosis , a process that utilize the host cell actin cytoskeleton. The opsonisation with the C3 component of the complement can promote phagocytosis.

How the pathogen infect host cells

Once phagocytosed by the alveolar macrophages,the bacteria produce virulence factors that enhance phagocytosis and helps in intracellular survival and proliferation. Legionella lipopolysaccharide and rcp gene that codes for a lipid A modifying enzyme appears to promote the intracellular survival,growth and infection.The organism reside within a nascent phagosome(Legionella containing vacuole)and doesn't fuse with lysosome or endosome, thereby avoiding acidification and degradative enzymes. After sufficient intracellular replication, it kills the macrophage and enters the extracellular tissue, rephagocytosed by other macrophages and thus the amplification takes place in lungs. Neutrophils, additional macrophages, RBCs infiltrate the alveoli, capillary leakage results in edema.Chemokines and cytokines released by macrophages trigger the inflammatory response.Type 2 secretory system in the organism is involved in release of degradative enzymes and animal models suggest that there is another secretory system,type 4b.The organism causes interstitial atypical pneumonia with an incubation period of 2 to 10 days.Disease manifestations include non productive cough,chest pain, high fever,sometimes diarrhea.

How the pathogen transmit to a new host.

From the environment, the organism enters the host through inhalation of infected aerosol(which can happen in cooling towers,water spa,water fountain )or micro aspiration of contaminated water( which can happen during nasogastric tube irrigation with tap water).Person to person transmission will not occur.