The Microbe, the Infection Enigma, and the Host
Jean-Laurent Casanova1,2,3,4,5, Laurent Abel3,4,5
1Howard Hughes Medical Institute, New York, NY, USA.
Abstract:
Human infectious diseases are unique in that the discovery of their environmental trigger, the microbe, was sufficient to drive the development of extraordinarily effective principles and tools for their prevention or cure. This unique medical prowess has outpaced, and perhaps even hindered, the development of scientific progress of equal magnitude in the biological understanding of infectious diseases. Indeed, the hope kindled by the germ theory of disease was rapidly subdued by the infection enigma, in need of a host solution, when it was realized that most individuals infected with most infectious agents continue to do well. The root causes of disease and death in the unhappy few remained unclear. While canonical approaches in vitro (cellular microbiology), in vivo (animal models), and in natura (clinical studies) analyzed the consequences of infection with a microbe, considered to be the cause of disease, in cells, tissues, or organisms seen as a uniform host, alternative approaches searched for preexisting causes of disease, particularly human genetic and immunological determinants in populations of diverse individuals infected with a trigger microbe.
Insights
Infectious disease treatment advanced rapidly, but understanding why only some people get sick remains a challenge. Research now explores host genetics and immunity to solve the infection enigma.
Area of Science:
- Infectious Disease Epidemiology
- Host-Pathogen Interactions
- Genetics of Infectious Disease
Background:
- The germ theory of disease led to effective treatments for infectious diseases.
- However, understanding why most infected individuals remain asymptomatic is lacking.
- This highlights the 'infection enigma' and the need for host-centric research.
Purpose of the Study:
- To investigate the underlying causes of disease severity in infectious diseases.
- To explore host factors, particularly genetic and immunological determinants, in disease outcomes.
- To shift focus from solely microbial triggers to host susceptibility.
Main Methods:
- Review of canonical approaches (in vitro, in vivo, clinical studies) focusing on microbial impact.
- Analysis of alternative approaches examining pre-existing host factors in diverse populations.
- Investigating human genetic and immunological variations in individuals exposed to infectious agents.
Main Results:
- Canonical methods adequately addressed microbial roles but overlooked host variability.
- Infection outcomes vary significantly among individuals despite exposure to the same microbe.
- Pre-existing host factors, including genetics and immunity, are crucial in determining disease.
- Most infected individuals do not develop severe disease, indicating a host-driven component.
Conclusions:
- Understanding infectious disease requires a deeper investigation into host determinants beyond the microbe.
- Human genetic and immunological factors play a critical role in disease manifestation.
- Future research should prioritize host-based solutions to the infection enigma.
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