Lassa fever pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Overview

Lassa fever may be transmitted from either infected animals (typically rodents) or humans following exposure to body fluids and excretions/secretions from the respiratory tract or GI tract. Following transmission, Lassa virus infects the endothelium and replicates intracellularly using an L-polymerase enzyme and nucleocapsid protein NP, which synthesize ribonucleoprotein (RNP) that produces mRNA and antigenomic RNA required for transcription. NP protein helps the virus evade the host immune system. Following transcription, vascular dysfunction ensues, resulting in the development of clinical manifestations of the disease. Although all organs may potentially be infected, the liver is a common target organ, and hepatitis/hepatic necrosis is typical following Lassa fever infection.

Transmission

Animal to Human

• Infection in humans typically occurs via exposure to animal (typically rodent) excrement through the respiratory or gastrointestinal tracts.
• Inhalation of tiny particles of infected aerosol is thought to be the most significant means of exposure, but transmission through direct exposure of infection to skin wounds or mucous membranes.
• Handling of dead infected animals has also been associated with the transmission of Lassa virus.

Human to Human

• Lassa virus may be transmitted following exposure to blood, tissue, secretions (including breast milk), or excretions of an infected individual.
• The virus cannot be transmitted without the exchange of body fluids.

Cellular Pathogenesis

Host Cell Entry

• Following transmission, Lassa virus primarily infects the endothelial cells.
• The Lassa virus gains entry into the host cell by means of the cell-surface receptor the alpha-dystroglycan (alpha-DG), a versatile receptor for proteins of the extracellular matrix.
• Unlike most enveloped viruses which use clathrin-coated pits for cellular entry and bind to their receptors in a pH dependent fashion, Lassa virus instead undergoes cellular entry via endocytosis using alpha-dystroglycan receptor (ubiquitously expressed cell surface receptor), independent of either clathrin, caveolin, dynamin or actin.
• Once within the cell, the viruses are rapidly delivered to endosomes via vesicular trafficking. Once in contact with the endosome, Lassa virus evades endosomal degradation using envelope glycoproteins, which mediate a pH-dependent binding and membrane fusion.

RNA Synthesis

• Intracellular RNA synthesis is initiated within an L-polymerase enzyme, which utilizes viral RNA templates and nucleocapsid protein NP to synthesize viral ribonucleoprotein (RNP). Once synthesized, RNP is transmitted to the host cell cytoplasm, and transcription of mRNA and antigenomic RNA (agRNA).

Host Immune Response

• Lassa fever evades the host immune system by production of NP protein, which has an exonuclease activity and causes the inhibition of host type I IFN signaling.
• Endothelial dysfunction results in the release of pro-inflammatory cytokines and cell mediators, which in turn cause platelet dysfunction, hepatic necrosis, suppression of cardiac function, and development of Lassa fever-associated clinical manifestations, including facial edema, pleural and pericardial effusions, and hypovolemic shock.
• Lassa fever may potentially infect all organs, but the liver and auditory sensorineural system are commonly involved.
• Failure of the host to mount an adequate cellular immune response to control viral dissemination, along with disseminated replication in tissues and absence of neutralizing antibodies, results in host death. Prompt host immune response is critical for host survival, and fatal Lassa fever is often characterized by impaired or delayed cellular immunity.

Genetics

• Replication for Lassa virus is very rapid and demonstrates a temporal control.
• The initial replication step is transcription of mRNA copies of the negative (minus-sense) genome. This process ensures an adequate supply of viral proteins for subsequent steps of replication, as the NP and L proteins are translated from the mRNA.
• Following the initial replication step, the positive (plus-sense) genome then synthesizes viral complementary RNA (vcRNA) copies of itself. The vcRNA copies are then used to synthesize more mRNA and to serve as templates for the production of more negative-sense progeny. The mRNA synthesized from vcRNA are then translated to produce GP and Z proteins.
• This temporal control allows the spike proteins to be produced last, and therefore, delay recognition by the host immune system.

Gross Pathology

Lassa virus commonly involves the liver and results in hepatocellular necrosis and apoptosis. Other organs may be involved, and Lassa fever infection may manifest with the following:

• Splenic necrosis
• Adrenocortical necrosis
• Mononuclear interstitial myocarditis
• Pulmonary alveolar edema with capillary congestion and mild interstitial pneumonitis
• Lymph nodal sinus histiocytosis
• Gastrointestinal mucosal petechiae
• Renal tubular injury
• Interstitial nephritis

Microscopic Pathology

Typical features of Lassa fever-associated hepatitis include the following:

• Acidophilic necrosis
• Apoptotic changes
• Ballooning degeneration
• Pycnotic nuclei
• Microvascular changes
• Councilman bodies (intracellular inclusion bodies)

The images below display key features of microscopic pathology of Lassa virus.

• 

  This photomicrograph demonstrates hepatitis caused by the Lassa virus, using toluidine-blue azure II stain. Retrieved from the Public Health Image Library (PHIL) of the Centers for Disease Control and Prevention.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

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  This transmission electron micrograph (TEM) demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever. The presence of a typical Councilman body, pycnotic nuclei in an area of acidophilic necrosis, and microvacuolar fatty changes are noted.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Scanning electron micrograph (SEM) demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever. A zone of acidophilic necrosis, and numbers of pycnotic nuclei are noted.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  Sudan III-stained photomicrograph demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever. Microvacuolar fatty necrosis is noted.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.

• 

  This photomicrograph demonstrates hepatitis caused by the Lassa virus, using toluidine-blue azure II stain, magnified 500X.Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.