Another question is why the influenza virus causes lethal viral pneumonia in some people and a mild or inapparent upper respiratory tract infection in others. For example, Schulman and Kilbourne demonstrated that mice which had recovered from an H1N1 infection had lower mortality, decreased pulmonary titers, and less extensive pulmonary pathology than did either naive or influenza B-primed mice. This phenomenon is referred to as heterotypic (or heterosubtypic) immunity. While heterotypic immunity clearly is important in animal (mouse and ferret) models of influenza, there are few studies of its role in man. The limited studies of heterotypic immunity in humans have clearly shown that infection with one strain of influenza A virus will not prevent infection with a shifted influenza A virus; however, epidemiological studies suggest that the subsequent disease course in individuals infected during the same season may be less severe. Further studies by Robert Yetter in the
University of Florida labs have provided another explanation that is probably particularly important in influenza in young children. To study influenza infection in mice, most researchers anesthetize the animals, paralyzing gag and cough reflexes. When these animals are then infected by nose drops containing virus, 25% to 50% of the dose goes direcfly into the lungs. This is an overwhelming inoculum that produces a lethal viral pneumonia. Yetter showed that when such drops are given to conscious mice, the gag and cough reflex prevents drops from reaching the lungs: only the nose is initially infected. He found that the LD50 for the conscious mouse was 2,000 times that for the anesthetized mouse.
As shown in Figure 4, Yetter also found that virus given to conscious mice immediately infected the nose, took three days to spread to the trachea, and then took five days to get into the lungs. This may give the immune system enough time to protect the host from fatal viral pneumonia. Control mice, infected while anesthetized, shed virus from the nose, trachea, and lung on day 1 and died by day 7. Thus, one possible factor in the severity of influenza is the initial site of infection.
In humans, the initial site of Influenza infection depends on the mode of spread. If virus is spread by fomites such as fingers or direct large-droplet spray from a sneeze, only the upper respiratory tract will be infected initially. Inhaled large droplets have too much momentum to make the twists and turns of the respiratory tract and thus are likely to be trapped by nasal mucosa. Small droplets, on the other hand, tend to stay in the mainstream of inhaled air and can travel all the way to the lungs to establish infection.
Perhaps that is what happened to a young pathologist in Tampa, Florida, in the late 1960s: Because he did not wear a mask while autopsying a patient who had died of influenza, the bone saw he used may have produced a small-droplet aerosol that led to initial infection of his lungs and hence viral pneumonia, from which he died within five days.
In addition to a correlation between the site of initial infection and the type of disease, Yetter showed that heterotypic immunity plays a key role in determining the nature and severity of influenza infection. Heterotypic immunity is produced by previous infection with a type A influenza virus of a different serotype. For example, a person (or an experimental animal) infected with type A H3N2 influenza virus will have heterotypic immunity to type A HlN1 virus but not to a type B influenza virus. This heterotypic immunity does not prevent infection but does speed recovery and decrease severity.
Yetter showed that if heterotypically immune mice were infected while conscious, viral infection of the nose never spread to the trachea or lungs (see Figure 4). Thus, heterotypic immunity restricts influenza infection to the original site. Jonathan Yewdell, John Bennink, Geoffrey Smith, and Bernard Moss at the National Institute of Allergy and Infectious Diseases have shown that heterotypic immunity is mediated by cytotoxic T lymphocytes against viral nucleoprotein, which is antigenically cross-reactive among all type A influenza viruses.
This helps explain why influenza is more severe in children than in young adults (Figure 5). In previously uninfected children, the virus will spread throughout the respiratory tract. Once such children survive their first type A flu, heterotypic immunity helps control the severity of subsequent infections.
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