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Conference Summary
Infectious Etiologies of Chronic
Diseases: Focus on Women1
Siobhán O'Connor,*
DeLisa Fairweather,† Brad D. Pearce,‡ and Sonja Rasmussen*
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; †Johns
Hopkins University, Baltimore, Maryland, USA; and ‡Emory University School
of Medicine, Atlanta, Georgia, USA
Suggested
citation for this article
Infections can directly or indirectly cause chronic conditions through
progressive pathology (e.g., chronic infection, inflammation, immunity,
malignant transformation), sudden permanent insults (e.g., West Nile virus
poliomyelitis paralysis), or by predisposing people to noninfectious sequelae
(e.g., neurologic consequences of preterm birth). Bacteria, parasites,
prions, viruses, and fungi may be the single or one of several factors
contributing to chronic disease; one organism can cause more than one
syndrome, and diverse pathogens produce similar syndromes as pathways
to disease converge (1). Certain potential outcomes disproportionately
affect women (e.g., autoimmune diseases), and in some settings, detection,
prevention, or treatment efforts (e.g., ocular trachoma, underdiagnosed
genital infections) may marginalize women. Women's activities can also
increase exposures to chronic disease pathogens (e.g., schistosomiasis
attributable to chores or agriculture), and gender can affect transmission
(e.g., increased male-to-female transmission of human T-cell leukemia
virus–1). Preventing maternal infections may further minimize chronic
disease and neurodevelopmental disorders in offspring.
Are Women's
Autoimmune Diseases Really Autoimmune?
Systemic and organ-specific autoimmune diseases, such as rheumatoid arthritis
and myocarditis, are the leading cause of death in women >65 years
of age (2). They affect 14–22 million people (5%–8% of
the population) in the United States (3) and millions
more worldwide. In autoimmunity, the immune system may attack or damage
self-tissues with autoantibodies and autoreactive T and B cells. However,
the indolent nature of most autoimmune diseases makes determining infectious
triggers difficult. Animal models help to understand such links. For example,
transfer of disease by autoantibodies and immune cells from affected animals
indicates the immune-mediated nature of these syndromes (4–6).
Toll-like receptors and the innate immune system, critical components
of the normal human response to infection, are essential to naturally
and experimentally induced autoimmunity. Genetic and other factors affect
susceptibility to both infection and autoimmune disease. For example,
coxsackievirus B3 induces viral myocarditis in susceptible mice. Certain
cytokines (interleukin [IL]-1β and tumor necrosis factor [TNF]-α),
but not viral replication, correlate with cardiac inflammation and can
overcome resistance to chronic myocarditis (7–9). These
findings suggest that, while infection may trigger autoimmunity, immune
processes drive disease progression. Estrogen amplifies the immune response
to coxsackievirus B3 in susceptible mice, increasing TNF-α and IL-4
levels (unpub. data), which is perhaps consistent with women's predisposition
to autoimmune disease. Identifying triggers, including infection, and
early markers of autoimmunity are important goals for preventing onset
of or disrupting progression to autoimmune disease.
Infection
Connection in Neurodevelopmental Disorders
Intrauterine infections are known causes of congenital defects worldwide.
Infections during the time of fetal brain development might also contribute
to neuropsychiatric disorders, including schizophrenia. Studies linking
various gestational insults (including infections) and subtle premorbid
behavioral alterations to adult schizophrenia implicate a neurodevelopmental
origin. However, the long latency between putative infection or insult
and the emergence of psychotic symptoms complicates establishing direct
links. While most reports have been ecologic studies without confirmed
maternal infection, Brown et al. (10) found that 20.4%
of persons with a documented in utero exposure to rubella developed an
adult schizophrenia spectrum disorder. Experimentally, lymphocytic choriomeningitis
virus infection in a neonatal rat model produces some latent changes similar
to those of schizophrenia, e.g., hippocampal atrophy and impaired inhibitory
GABA neurotransmission (11); blocking IL-1 partially
attenuates the hippocampal cell loss. Inflammatory cytokine responses,
perhaps amplified by immunogenetic abnormalities, may be a common thread
linking intrapartum infections and noninfectious gestational and obstetric
complications to neurodevelopmental disorders (12).
Keys to
the Future
A continuum from acute infection to chronic disease exists, and each
stage is an opportunity to prevent or minimize an avoidable fraction of
chronic disease—that resulting from infectious disease. Crucial steps
include identifying infectious etiologies and cofactors, determining persons
(including women) at risk for infection or outcome, and implementing measures
that minimize chronic sequelae. Research incorporating longitudinal studies
that precede clinical disease must support evidenced-based conclusions
and actions. The benefits to women could be substantial.
References
- Knobler SL, O'Connor S, Lemon SM, Najafi M, editors.
The infectious etiology of chronic diseases: defining the relationship,
enhancing the research, and mitigating the effects—workshop summary.
Forum on Emerging Infections, Institute of Medicine. Washington: The
National Academies Press; 2004.
- Walsh SJ, Rau LM. Autoimmune
diseases: a leading cause of death among young and middle-aged women
in the United States. Am J Public Health. 2000;90:1463–6.
- National Institutes of Health. Autoimmune diseases research plan [monograph
on the Internet]. 2003 Jul [cited 2003 Mar 21]. Available from http://www.niaid.nih.gov/dait/pdf/ADCC_Report.pdf
- Fairweather D, Lawson CM, Chapman AJ, Brown CM, Booth TW, Papdimitriou
DM, et al. Wild
isolates of murine cytomegalovirus induce myocarditis and antibodies
that cross-react with virus and cardiac myosin. Immunology. 1998;94:263–70.
- Fairweather D, Rose NR. Type
1 diabetes: virus infection or autoimmune disease? Nat Immunol.
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infection to autoimmunity. J Autoimmun. 2001;16:175–86.
- Fairweather D, Yusung S, Frisancho S, Barrett M, Gatewood S, Steele
R, et al. IL-12
receptor beta 1 and Toll-like receptor 4 increase IL-1 beta- and IL-18-associated
myocarditis and coxsackievirus replication. J Immunol. 2003;170:4731–7.
- Lenzo JC, Fairweather D, Cull V, Shellam GR, Lawson CM. Characterization
of murine cytomegalovirus myocarditis: cellular infiltration of the
heart and virus persistence. J Mol Cell Cardiol. 2002;34:629–40.
- Lenzo JC, Fairweather D, Shellam GR, Lawson CM. Immunomodulation
of murine cytomegalovirus-induced myocarditis in mice treated with lipopolysaccharide
and tumor necrosis factor. Cell Immunol. 2001;213:52–61.
- Brown AS, Cohen P, Harkavy-Friedman J, Babulas V, Malaspina D, Gorman
JM, et al. Prenatal
rubella, premorbid abnormalities, and adult schizophrenia. Biol
Psychiatry. 2001;49:473–86.
- Pearce BD. Modeling the role of infections in the
etiology of mental illness. Clin Neurosci Res. 2003;3:271–82.
- Gilmore JH, Jarskog LF. Exposure
to infection and brain development: cytokines in the pathogenesis of
schizophrenia. Schizophr Res. 1997;24:365–7.
1The following comments were made in presentations
by the above authors at the International Conference on Women and Infectious
Disease.
Suggested citation
for this article:
O'Connor S, Fairweather
D, Pearce BD, Rasmussen S. Infectious etiologies of chronic diseases:
focus on women [conference summary]. Emerg Infect Dis [serial on the Internet].
2004 Nov [date cited]. Available from http://www.cdc.gov/ncidod/EID/vol10no11/04-0623_07.htm
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