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Pathogenesis 97

NWS strain disseminates to the brain by hematogenous spread when given intraperitoneally but reaches the central nervous system via the sensory neurons when the virus inoculum is placed in the nose (Flint 2004). The latter has been demonstrated with the Hong Kong H5N1 virus as well (Park 2002).

What is the initial host response?

Although a frequent disease, the specific inflammatory patterns or regulation of immune response and the pathogenesis of cytopathic effects in human influenza is incompletely understood. Most evidence comes from animal studies, where avian influenza is a disseminated disease. The pathophysiology of such models, however, may profoundly differ from that in humans.

Cytokines and fever

A central question is how an infection essentially localized to the respiratory tract can produce such severe constitutional symptoms. As in many other infectious diseases, it is the unspecific and adaptive immune response that contributes substantially to the clinical signs and symptoms in influenza and finally to the control of infection. These immune mechanisms can lead to both localized as well as systemic effects. Cytokines, rapidly produced after infection by epithelial and immune cells of the respiratory mucosa, are local hormones that activate cells, especially within the immune system. Chemokines are a subset of cytokines that act as chemoattractants for cells of the immune system. For example, influenza infection induces in human plasmacytoid and myeloid dendritic cells a chemokine secretion program which allows for a coordinated attraction of the different immune effectors (Piqueras 2005, Schmitz 2005). The most important cytokines serve as endogenous pyrogens and are involved in the pathogenesis of fever: IL-1α/β, TNF α/β, IL-6, interferon (IFN) α/γ, IL-8, and macrophage inflammatory protein (MIP)-1α.

Most of these cytokines have been detected in nasopharyngeal washes of humans who have been experimentally or naturally infected with influenza (Brydon 2005). It is proposed that these cytokines, produced locally or systemically following interaction of exogenous pyrogens (e.g. influenza) with phagocytes, reach the central nervous system. There is a small area in the hypothalamus, called the Organum vasculosum laminae terminalis, which has a reduced blood-brain-barrier and allows the passage of pyrogens. At this site, in a dose-dependent manner, they induce the production of prostaglandins and especially prostaglandin E2. These mediators increase the thermostatic set point and trigger complex thermoregulatory mechanisms to increase body temperature. The fact that none of the cytokines mentioned above correlated with the severity of disease in influenza infection, argues in favor of their pleiotropy and cross-talk amongst signaling pathways.

The relevance of cytokines may also differ between influenza strains or individuals. Influenza infections with the Hong Kong H5N1 strain from 1997 have been proposed to potently induce pro-inflammatory cytokines (particularly TNFα) by NS gene products (Cheung 2002, Lipatov 2005, Chan 2005). Studies aimed to identify other virion components that induce cytokine release revealed that double-stranded (ds) RNA, either from lungs of infected mice or synthetically derived from influenza, were pyrogenic when injected into the CNS-ventricle of mice. Such dsRNA is released from infected cells when they die and thus may stimulate cytokine production. Recent studies indicate that dsRNA-sensing Toll-like receptor (TLR) 3 is ex-

98 Pathogenesis and Immunology

pressed on pulmonary epithelial cells and that TLR3 contributes directly to the immune response of respiratory epithelial cells (Guillot 2005, Akira & Takeda 2004). Interestingly, in humans the initiation of an innate immune response against influenza appears to be at least as dependent on sensing single stranded RNA via TLR 8 than on detecting dsDNA by TLR 3. Virus particles can also be pyrogenic, as virosomes depleted of RNA but including viral lipid, hemagglutinin, and neuraminidase may induce fever. Individual virion components were, however, not pyrogenic probably explaining why whole virus vaccines can produce influenza-like symptoms while subunit vaccines do not (Brydon 2005).

Respiratory symptoms

Hyperreactivity of the bronchial system (Utell 1980, Little 1978), obstruction predominantly of small airways (Hall 1976) and impaired diffusion capacity (Horner 1973) is common in influenza infection. Hyperreactivity and broncho-obstruction may persist for a prolonged period, especially in allergic disease (Kondo & Abe 1991), and might be a result of a pro-inflammatory cytokine profile which interferes with the ability to induce tolerance to aerosolized allergens (Tsitoura 2000).

In human influenza infection, severe alveolar inflammation presenting as primary viral pneumonia, is rare. It usually presents with extended inflammation of both lower and upper respiratory tracts with loss of ciliated cells, and imposed hyperemic or hemorrhagic areas on hyaline membranes and infiltrates of neutrophils and mononuclear cells (Yeldandi & Colby 1994).

In contrast to primary viral pneumonia, bacterial superinfection is common in human influenza and causes serious morbidity and mortality predominantly in elderly adults. Several factors have been identified, which could explain the increased risk for bacterial infection of the respiratory tract, including damage of columnar epithelial cells with disruption of the epithelial cell barrier (Mori 1995), decreased mucociliary clearance (Levandovsi 1985), enhancement of bacterial adherence (McCullers 2002), and functional alteration of neutrophils (Abramson 1986, Cassidy 1988).

Cytopathic effects

Human influenza leads to complex cytopathic effects, predominantly at the columnar epithelial cells in the respiratory tract, that result in acute disease of lung and airways. Infection and viral replication of the influenza virus in the respiratory tract leads to cell damage induced by downregulation of host cell protein synthesis (Katze 1986, Sanz-Esquerro 1995) and apoptosis (Wiley 2001a). The latter, also called programmed cell death, is a series of defined cellular events that eventually results in the efficient removal of the cell and its contents. Apoptosis can be triggered by different mechanisms and is characterized by several morphological changes, including cytoskeleton disruption, condensation of cytoplasm and chromatin, loss of mitochondrial function, DNA fragmentation, and ultimately the formation of small membrane bound particles known as apoptotic bodies, which are cleared by phagocytic cells such as macrophages and dendritic cells.

The influenza virus-induced apoptosis is mediated by both Fas-mediated mechanisms and Fas-independent signals, such as the formation of FADD/caspase-8 complex by protein kinase R (PKR), which initiates a caspase cascade. PKR is a key regulatory component in many apoptotic pathways and is induced by IFN and acti-

Pathogenesis 99

vated by dsDNA (Brydon 2005). As a third pathway to apoptosis, influenza activates transforming growth factor (TGF)-β via viral neuraminidase. NA can activate latent TGF-β on the cell surface by facilitating cleavage of TGF-β into its active form. TGF-β initiates a signaling cascade leading to the activation of the c-Jun N- terminal kinase (JNK) or stress activated protein kinase (SAPK), resulting in the activation of transcription factors and upregulation of pro-apoptotic gene expression. This pathway, together with the effects on the mitochondrial membrane stability of a small protein, encoded by an alternative +1 reading frame in the PB1 protein (Chen 2001), has been implicated in the apoptosis of lymphocytes and could explain the lymphopenia observed during acute infection.

Lung tissue injury following infection with the influenza virus has been associated with cellular oxidative stress, generation of reactive oxygen species (ROS), and the induction of nitric oxide synthetase-2, which leads to the formation of toxic reactive nitrogen intermediates. Anti-oxidants, however, had little effect on apoptosis in bronchiolar cell lines in vitro.

Symptoms of H5N1 infections

Avian influenza is an infectious disease of birds caused by type A strains of the influenza virus. To date, all outbreaks of the highly pathogenic form have been caused by influenza A viruses of subtypes H5 and H7. It is currently unknown whether avian influenza in humans (H5N1) has the same cytopathic effects as mentioned above. Only a few studies in severe or fatal cases have been performed. However, asymptomatic or mild symptomatic disease is possible (Buxton Bridges 2000, Katz 1999) and its incidence may be underestimated.

The most common initial symptoms of H5N1 influenza in humans were high fever, and, in those patients referred to a hospital, pneumonia, pharyngitis, intestinal symptoms, conjunctivitis, and acute encephalitis (Yuen 1998, Tran 2004, Yuen & Wong 2005). Adult patients with initial signs of pneumonia often progressed to an ARDS-like disease. In fatal cases of H5N1-influenza, reactive hemophagocytic syndrome has been described as a prominent feature. Beyond pulmonary disease with organizing diffuse alveolar damage and interstitial fibrosis, extrapulmonary involvement has been described as extensive hepatic central lobular necrosis, acute renal tubular necrosis and lymphoid depletion (To 2001), although there was no virus found on isolation, reverse transcription polymerase chain reaction and immunostaining respectively. Soluble interleukin-2 receptor, interleukin-6 and inter- feron-gamma were increased. In addition, tumor necrosis factor-alpha mRNA was seen in lung tissue in other cases with H5N1 influenza in humans (Uiprasertkul 2005).

In comparison to human H1N1 viruses (Hayden 1998), the Hong Kong H5N1 strain from 1997 has been proposed to potently induce pro-inflammatory cytokines including IL-10, IFNβ, RANTES, IL-6 and particularly TNFα by NS gene products (Cheung 2002, Lipatov 2005, Chan 2005). The authors of these studies postulated that in a fatal human infection with the avian H5N1 subtype, initial virus replication in the respiratory tract triggers hypercytokinemia complicated by a reactive hemophagocytic syndrome, which might be a different pathogenesis of influenza A H5N1 infection from that of usual human subtypes (To 2001). Bacterial superinfection has not been found in fatal cases of H5N1 avian influenza (To 2001). This observation might be a bias of the early fatal outcome of these most severe cases, which hypothetically did not allow for the development of superinfection.