Experimental Models of Infectious Diseases

Nadia ZamanKaren Slattery

What are Infectious Diseases?• Infectious diseases are caused by pathogenic microorganisms, such as

bacteria, viruses, parasites or fungi; the diseases can be spread, directly or indirectly, from one person to another. Zoonotic diseases are infectious diseases of animals that can cause disease when transmitted to humans.

Why Study Infectious Diseases?

• Infectious diseases represent an increasingly important cause of human morbidity and mortality throughout the world

• WHO – Infectious diseases cause about 23% of deaths every year• Need to limit the impact of these diseases

Importance of Studying Infectious Diseases

• We need to be able to study the microorganism’s interactions with the host

• Antibiotic resistance is an increasing problem and vaccines do not working on everything

Need new therapies!

• Use of experimental models is extremely important in studying infectious disease due to the ethical issues surrounding the exposure of humans to potentially lethal agents

Types of Experimental Models

1. In Vitro 2. In Vivo

3. Human Studies

In Vitro Models• Infect the cells or tissues with the infectious disease• Can study specific pathogen – host interactions

– Cytokine production– Gene expression – Metabolism – Development of/ response to therapy

Case Study: HCV Infection in Hepatocyte Microislands

• Microislands of hepatocytes surrounded by stromal cells

• Supports persistent HCV replication for >12 days and the generation of infectious virions

• Also supports the stages of liver infection by the malaria parasites Plasmodium falciparum and Plasmodium vivax

Ultimately in vitro models do not accurately depict an infected living animal: lack the homeostatic mechanisms and the diverse, interconnecting pathways in animals In vitro experimental success often fails to translate in vivo.

• Simplicity: can focus on specific aspects of infectious disease

• Species specificity: can study human response

• Convenience and cost: easier to perform, cheaper

Advantages & Disadvantages

In vivo modelsIn vivo: Processes performed or taking

place in a living organism

In biomedical research we primarily use animal models; most commonly, rodents

Animal models used in the research of infectious diseases have specific test conditions in which the model may have an inbred or induced disease that is similar to a human disease

Exposure

Infection

Illness

Recovery Sequelae Death

?

Case Study: Helicobacter pylori

• H. pylori is a major cause of certain diseases of the upper gastrointestinal tract.

• It is transmissible, although the exact route of transmission is not known.

• Mongolian gerbils inoculated with H. pylori orally and observed over 1 year

• Studied development and infection by H. pylori and its association with gastric carcinogenesis

Alternative Animal Models: Zebrafish

• The immune system is highly homologous between zebrafish and humans and therefore they are very favourable experimental models

• During their early life stages, zebrafish are very transparent and are well suited for in vivo imaging and studying the host-pathogen interactions genetically

Advantages of In vivo Models• Reduced harm to humans• Ensuring the safety of drugs and other substances• Most accurate way to learn about effects of diseases in living bodies

Disadvantages of In vivo Models• Increased harm to animals involved• Expensive• Legal paperwork• Limited by the fact that animals are not humans

Human Studies

• Studying patients actually infected with the disease

Blood samples Smears Biopsies Retrospective analysis

E.g. the expansion of memory Th1 cells in S. aureus infection

Case Study: Clumping Factor B in S. aureus Nasal Colonization in Humans

• Inoculated the nose of 16 human volunteers with either WT or ClfB KO mutant

• Mutant strain eliminated from the nares much faster • Some of the WT remained at the end follow up

ClfB is a major determinant for nasal-persistent carriage: candidate for decolonization strategies

Thanks for listening!