Flip the Script: Which Came First, Germs or the Infection?

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Roughly 99.5% of people born before 1980 are infected with herpes zoster, yet only 33% will develop its clinical manifestation: shingles. The Institute for Health Metrics and Evaluation estimates that 98% of people in the U.S. have been infected with COVID, but roughly 30% of our population has been symptomatic to the extent that they are registered as “cases.” It's time to discuss the infection enigma - “the puzzling observation that only a small minority of infected people die from infection or even develop clinical disease.”

This article summarizes an opinion piece in the Proceedings of the National Academy of Science. It explores the history and language of the “standard model” of infectious disease, SIR - Susceptible, Infectious, Recovered. 

Infectious – the Germ Theory

In 1890 Robert Koch published his criteria for the causal relationship between microbes and disease, setting the stage for the germ theory of disease. The influence of this theory cannot be overestimated – it has explained our global life expectancy remaining stubbornly stuck at two to three decades. It allows us to act upon that information with “the advent of hygiene, vaccines, aseptic surgery, and antibiotics….” His first postulate states that a given pathogen is found in all patients with the corresponding disease and not in healthy individuals. But as herpes zoster and COVID clearly demonstrate, that is not true – many patients are host to the microorganism, but far fewer have clinical manifestations, “the corresponding disease.”

Tuberculosis is another example of an "infection enigma." Mycobacterium tuberculosis, the infectious agent of the continuing global problem of tuberculosis, is estimated to reside in 25% of the global population. Yet 90% of those individuals have a latent form, where the mycobacterium is present, it is not contagious, and the patient has no clinical manifestations. René Dubos, more than 70 years ago, recognized these “silent” infections must be due to

“a recent causal “weakening” of the sick host, after infection, but before the development of disease.”

Those weakenings, or as he described, “changing circumstances,” were attributable to external environmental stressors, “ecological” in the sense that the stress originated in the environment, which could also, in turn, be modified by the host. Vaccines, social distancing, and masks are all environmental modifications. 

Susceptibility Moving toward genetics

Sickle cell anemia or sickle cell disease (SCD) is an inherited disorder, an abnormality in the hemoglobin molecule that reduces oxygen transport ability and causes clumping and clotting. The resultant clumps and clots obstruct blood flow in the smaller vessels and provoke extremely painful sickle cell crises damaging organs like the kidneys. In 1949 a South African geneticist, Anthony C. Allison, was faced with a puzzle. When the hemoglobin abnormality of SCD is found in both genes contributed by the parents, the disease is fatal. But he discovered that upwards to 20% of the Kenyans he assessed had the far less lethal trait, one, not two, abnormal genes. He reported in 1954 that the underlying reason for such a high percentage was that “sickle cell trait provides large African populations with 10-­fold greater protection against the risk of cerebral malaria…[a] population level has never been surpassed by candidate gene or genome-­wide approaches.”

Several other notable examples of susceptibility to infections and our underlying genetics exist.

  • Bacterial appendicitis is infectious but not contagious. There are familial clusters of appendicitis.
  • Studies of tuberculosis in twins from the 30s and 40s show a more significant “sharing” of TB with genetically identical (monozygotic) twins at 90% than dizygotic twins, born with differing genetics, at 20%
  • The 1980 HIV epidemic demonstrated how an acquired immunodeficiency could result in specific rare infections, like pneumocystis pneumonia (PCP), caused by the fungus Pneumocystis jirovecii. Similarly, the immunosuppression from drugs used to suppress rejection in transplantation resulted in infections labeled “opportunistic.”

All of these instances, from recognizable, overt immunologic compromise, strongly suggest a role for genetics in increasing or decreasing the susceptibility of a host to an infectious organism.

Immunity is a spectrum

Not all genetic errors affect every individual with the error – a genetic finding termed incomplete penetrance (complete penetrance affects all individuals with the error). The presence of a BRCA (BReast CAncer) gene mutation reduces tumor suppression elevating the risk of breast and ovarian cancer in those with the mutation. Women with a BRCA1 mutation have a penetrance, a clinical manifestation, of 55 to 72%; those with BRCA2 have a penetrance of 45 to 69%.

Some inborn errors occur in cytokines; the small protein foot soldiers invoked in immunity's inflammatory response. Job’s Syndrome, a rare syndrome involving an error in the interleukin cytokine, results in recurrent skin staph infections. [1] Our immunologic responses are not always correct, and we may develop antibodies to ourselves, termed autoantibodies. The presence of autoantibodies may mimic inborn errors in cytokines by reducing the numbers and effectiveness of the normal cytokines, creating an “autoimmune phenocopy” of a disease.

Antibodies to one of the interferons (IFN-­α), another of the cytokines involved in our immune defense against viruses, is present in about 1% of adults under age 65 but increase to 4 to 7% in older populations. In a study of 3,595 hospitalized patients with “severe” COVID, autoantibodies to IFN-­α were found in 13.6% and were present in 18% of the patients who died.

In a new study reported in Nature, the same research group identified a variant of the HLA gene that confers a more robust immunity to COVID. In their study, 13,000 individuals in a donor registry, whose genes had been characterized were found to be positive for COVID. But 10% of those individuals were symptom-free. Roughly 20% of these symptom-free individuals had a specific mutation of their HLA-B gene that made them “especially potent at clearing SARS-CoV-2.” And when that mutation, which has an incidence of roughly 10% in those with European ancestry, is homozygous (coming from both mother and father), it increases the likelihood of remaining asymptomatic in the presence of a positive COVID test 8-fold.

A new paradigm

“It is, admittedly, difficult to measure the weights of causal factors, and comparing the respective contributions of the germ and host theories is intellectually challenging.”

It is the nature of scientific knowledge to build upon the work already done. The development of the germ theory as the explanation of infection has served us well, but it was developed before we had knowledge of immunity, let alone an immune system. For all its explanatory power, the germ theory could not incorporate what Donald Rumsfeld characterized as the “unknown unknowns.” Our understanding of immunology has changed substantially since Robert Koch penned his postulates 100+ years ago.

Our words describing our science are filled with metaphors that can both enhance and hamper understanding. The concept of “opportunistic infection,” when applied to patients with HIV and those undergoing chemotherapy, allowed us to pinpoint therapy but hampered an understanding that laboratory testing may not always be sufficient to easily recognize immunodeficiency.

The early deaths from COVID involved the elderly frail housed communally in nursing homes. It may well be that frail, based on a description of our musculoskeletal system, is a more general category encompassing alterations in our immune, overt or covert, that enhance susceptibility. 

“By reducing host defense and host deficiency to visible features and abnormalities, respectively, of blood leukocytes and their products,” we may have blinded ourselves to seeing the unknown unknowns – the genetic changes that increase or decrease our susceptibility to the clinical consequences of the microbes within us. We needn’t abandon Koch’s postulates, but we need to make room for what Rene Dubos described as changing circumstances. Among those circumstances, we must consider our underlying genetic predisposition, inherited or acquired, apparent or not, in our immune responses.

The use of the terms immunocompromised and "opportunistic" infection may have outlived their explanatory power. There is increasing evidence that we are all immunocompromised in one way or another and that the risk of an "opportunistic" infection may lie within our genes. 

[1] It's named after the biblical Job, whose faithfulness was tested by an affliction with draining skin sores and pustules.

Source: From second thoughts on the germ theory to a full-blown host theory PNAS DOI: 10.1073/pnas.2301186120