Lecture 6 - Identifying Host Factors Flashcards
How is virulence considered?
In the context of the host
As a relative term
How can host determinants be found? 1) 2) 3) 4)
1) Introduce immune or susceptible antibodies or cells into host animal
2) Deplete host factors with antibodies
3) Deplete host factors using knockout mice
4) Deplete host factors with a transgene
How to identify a host determinant
1)
2)
3)
1) Alter a mouse in a certain way (factor depletion using antibodies, etc)
2) Infect altered mouse, normal mouse with pathogen
3) Observe LD50, ID50, bacterial growth, pathology, transmission, etc
What is iNTS?
Invasive non-typhoidal salmonellosis
Evolution of invasive non-typhoidal salmonellosis
1)
2)
1) Salmonella enterica var. typhimurium was the leading cause of bacterimia in HIV+ patients in Malawi
2) Moved from infecting HIV+ to HIV- individuals
Causative agent of invasive non-typhoidal salmonellosis
Salmonella enterica var. typhimurium
Deficiencies predisposing to more severe salmonella infections
Deficiencies in IL-12, CD4
Invasive non-typhoidal salmonellosis mortality rate in children
45%
Difficulties in making a vaccine against Salmonella enterica var typhimurium (or treatment)
1)
2)
3)
1) Intracellular bacteria (vaccine immunity is normally antibody-mediated)
2) CD4+ T cells needed for a robust immune response - many patients are HIV+, therefore have little to no CD4+ T cells
3) Difficult to get antimicrobials into host cells
Cytokine that can control S typhimurium infection
IFNg
Issues with iNTS murine model
Lethal infection in mice within two to three days. Human infection lasts several weeks
Type of mice used in iNTS murine model
C57B6 mice
Solution to poor iNTS murine model
Use an attenuated strain of S. typhimurium that is less virulent in mice.
New strain controlled by mice within around 2 weeks
S. typhimurium experiment to determine controlling immune response
1)
2)
3)
1) Gather C57B6 mice with various immune deficiencies
2) Innoculate with a set amount of S typhimurium
3) Observe different courses of disease
Immunodeficiencies of C57B6 mice used in S typhimurium experiment 1) 2) 3) 4)
1) Deficient in IFNg, lymphocytes (RAG2 deficient). Very susceptible
2) Deficient in CD4+, CD8+ T cells. Susceptible (died)
3) Deficient in CD4+ T cells (chronic infection)
4) Mice lacking B cells, CD8+ T cells, MHC I, CD1. Course of disease is same as wild type mice