Download Evolutionary Aspects of Animal Model Use in Infectious Disease

Evolutionary Aspects of Animal
Model Use in Infectious Disease
Research
Stefan Niewiesk, DVM, PhD, DECLAM
Associate Professor
Department of Veterinary Biosciences
College of Veterinary Medicine
The Ohio State University
The MOUSE in research
C57BL/6
2/3 of all mice used
The MOUSE Model for Research
C57BL/6 mice produce most of
the data which form the basis for
our understanding of biology and
medicine
“Mouse concept”
Based on the fact that mice are the
best studied model system in
biomedical research everything
has to be “mousified”.
Evolutionary relatedness and animal
models
Animal model use is based on evolutionary
similarity between species:
•
•
•
•
Number and function of muscles and bones
Similarity of organ systems
Metabolism
Pain perception
Infectious Diseases drive Evolution
“To put the matter rather figuratively, it is much
easier for a mouse to get a set of genes which
enable it to resist Bacillus typhimurium than a
set which enables it to resist a cat”.
• J.B.S. Haldane (1949). Disease and evolution.
Supplement to La Ricerca Scientifica 19:68–76.
Distribution of malaria and malarial-resistance genes in the Old World. The current
distribution of endemic malaria (a) is paralleled by distributions of G6PD deficiency
(b), sickle-cell anaemia (c) and thalassaemia (d) in Africa, Europe, Asia and Australasia.
Balancing Selection in Human Evolution, Eric J Vallender,Welkin E Johnson, Wiley Online Library
Zoonotic diseases
• 20% of zoonotic diseases are from other
primates which are 0.5% of all species
• Transmission from animal to human,
susceptibility or resistance specific for the
pathogen and host
• Co-evolution between host and pathogen
Specificity of pathogen
Wolfe et al, Nature Reviews, 447, 279, 2007
Human pathogens drive evolution
in MICE????
“It makes sense for a mouse to get a set of
genes which enable it to resist Bacillus
typhimurium but why should it acquire
resistance against human pathogens it has
never met?”
S. Niewiesk
Animal Models for Infectious
Disease Research
Host – pathogen interaction:
• Animal model needs to be susceptible to the
pathogen under study in order to obtain
meaningful data
Immune response:
• Key elements of the immune response have to
be the same in animal model and human
Of Mice and Not Men: Differences between Mouse and Human Immunology
Javier Mestas and Christopher C. W. Hughes
The Journal of Immunology, 2004, 172, 2731-2738
Respiratory Syncytial Virus
• Pediatric population: 100,000 hospitalizations,
250 death per year
• Adult population: repeated infections with
bronchitis/tracheitis
• Over 65 years of age: second most common
viral cause of death, severe clinical disease
Problem: RSV in the mouse
• Challenge/clearance model
• No virus replication in upper respiratory tract
• Mouse: the epithelial lining of a bronchiole
consists primarily of Clara cells
• Human: unlike the mouse, this lining consists
of ciliated, columnar, respiratory epithelial
cells
RSV infection in human versus
mouse lung
human
Courtesy of J.L. Grieves and J. Durbin, NYU
mouse
Problem: RSV in the mouse
• Challenge/clearance model
• No virus replication in URT
• In consequence:
Vaccines work always well
Antivirals work well
Effect of vaccines and antivirals not predictive
for more susceptible animal models/human
Solution 1: natural pathogen
Mouse pneumovirus
Strains with different pathogenic potential
Low dose of inoculum (100 to 300 pfu)
Severe disease and inflammation
Lethal depending on inoculum
Pulmonary dysfunction for 3 to 4 weeks after
infection
• Not the “target virus”,
differences in pathogenesis
•
•
•
•
•
Solution 2: mouse-adapted pathogen
e.g. Influenza virus
• Alpha 2,3-linked sialic acid (SA) on epithelium
(human virus uses α-2,6-linked SA)
• Preference of avian influenza strains
• Mouse adaption of human strains necessary
• Selection for high pathogenicity/letality
• Lack of Mx proteins in cytoplasm
Solution 3: mice transgenic for human
receptor(s): Measles virus
• Mice are susceptible to intracerebral infection
• Mice are not susceptible to respiratory
infection
• MV uses human CD46 and CD150 as receptors
• Transgenic mice expressing either CD46 or
CD150 have been generated
• Transgenes do not change susceptibility
Cotton rats (Sigmodon hispidus)
 Inbred animals
 Commercially available
 About 350 genes sequenced
 Cytokines, chemokines and antibodies available from
R&D Systems
Monoclonal antibodies produced by Niewiesk lab,
large collection of cross-reactive antibodies
Susceptible to human pathogens:
Measles virus, respiratory syncytial virus,
human parainfluenza virus type 3, human metapneumovirus,
adenovirus, influenza virus and others
Staphylococcus aureus, Mycobacterium tuberculosis
Susceptible to infection but not
immune deficient
• Broncho-alveolar lymphoid tissue: rare
• Neutrophils in blood:
high
• Lymphocytes in blood:
low
RSV infection in nose and lung
Cotton rat
human
Courtesy of J.L. Grieves and J. Durbin, NYU
mouse
Virus replication at different ages
Age-dependent replication of respiratory
syncytial virus in the cotton rat
Curtis SJ, Ottolini MG, Porter DD, Prince GA.
Exp Biol Med. 2002; 227:799-802.
Comparison of B cell activation
after RSV infection in 6 to 8 week or
10 to 12 month old cotton rats
Bone marrow
*** p < 0.001, ANOVA (Analysis of Variance)
Similarities between humans and
cotton rats
•
•
•
•
•
•
•
Epithelium in lung (versus mouse)
Influenza virus receptor
Mx proteins
CD150 as measles virus receptor
Nitric oxide production by macrophages low
TLR-9 expression levels low
Hsp70 in tissue
Evolutionary Aspects of Animal Model Use in
Infectious Disease Research
 Evolution has not played a major role in shaping rodent models
 Host susceptibility
 Immune system
 Real life application versus knowledge generation
[email protected]
http://vet.osu.edu/cotton-rats-animal-model