**4. An aspect of Lassa virus pathogenicity**

copies of the negative sense gene, which makes sufficient deposition of virus proteins for the next stage of the replication process. Subsequently, L and NP proteins are translated from the mRNA. Copies of the viral complementary RNA (vcRNA) are made from the positive sense gene. Negative-sense progeny are produced by templates of RNA copies while mRNA is synthesized from it. The mRNAs produced from vcRNA are later translated to synthesize the Z and GP proteins. The temporal controls enhance the production of proteins spikes lastly,

The virus enters into the host cell by means of the cell-surface receptor (alpha-dystroglycan alpha-DG), which is a versatile receptor for proteins of the extracellular matrix [26]. Receptor recognition is based on a specific sugar modification of alpha-DG by a group of glycosyltransferases known as the LARGE proteins. Specific variants of the genes encoding these proteins appear to be under positive selection in West Africa, where the virus is endemic [26]. Enveloped viruses makes use of clathrin-coated pits mostly to enter cells and bind to their receptors in a pH dependent way while Lymphocytic choriomeningitis and Lassa virus makes use of the endocytotic pathway independent of caveolin, clathrin, dynamin, and actin. The viruses are quickly delivered once within the cell to endosomes via vesicular trafficking albeit, which is extensively independent of the tiny GTPases Rab5 and Rab7. pH-dependent membrane binding happens on contact with the endosome, which is mediated by the enveloped glycoprotein, and at the acidic pH, the endosome fuses the lysosome protein LAMP1

NP is the most dominant viral protein in virions and infected cells, which consists the main structural component of the viral ribonucleoprotein (RNP), which plays an important role in the RNA synthesis of the virus. Subsequently, the function required to assist replication of the virus, at least two viral proteins (NP and Z), have been proposed to modulate the cell response of the host to infection. Experimental data has showed that NP has a role in virusinduced inhibition of type I IFN signaling [27]. This role has been mapped to the C-terminal domain of NP with a folding that camouflages the DEDDH family of 3′-5′ exoribonucleases. The little RING finger protein Z is the arenavirus counterpart of the matrix (M) protein of other negative sense RNA viruses. The Z protein of lymphocytic choriomeningitis virus (LCMV) interacts with the promyelocytic leukemia (PML) protein as well as the eukaryotic translation initiation factor 4E (eIF4E) in infected cells and has been observed to function in the noncytopathic nature of LCMV infection and repression of cap-dependent translation [22, 28, 29]. Functional assays reported the exonuclease activity of LASV NP that has been

The replication cycle of Lassa virus is similar to the Old World arenaviruses. It was reported that virus internalization is limited upon cholesterol depletion. Dystroglycan, which is later cleaved into alpha-dystroglycan and beta-dystroglycan is initially expressed in most cells to mature tissues, which provides molecular bridge between the actin-based cytoskeleton and extracellular matrix (ECM) [26, 30]. After the viral agent enters the cell by alpha-dystroglycan-mediated endocytosis, low-pH domain enhances pH-dependent membrane bind and releases ribonucleoprotein of the virus (RNP) complex into the cytoplasm. The enzymatic machinery for RNA synthesis in arenaviruses is housed within a single L polymerase protein. This 250–450 kDa

and therefore, delay the recognition by host immune system [25].

154 Current Topics in Tropical Emerging Diseases and Travel Medicine

that yields in membrane bind and endosome escape [19].

proposed as important for its type I IFN counteracting functions [29].

The Lassa virus is well-known to cause Lassa fever [31]. Its symptoms include flu-like illness characterized by fever, general body weakness, cough, tonsillitis, headache, and gastrointestinal disorders. Hemorrhagic manifestations are other features of Lassa fever, which include vascular permeability [10].

The virus pathogenesis is still unclear, but it has been shown that the virus chiefly target the antigen-presenting cells (mainly dendritic cells) and endothelial cells [32]. Lassa virus infects most tissues in the human body when gained entry. It starts with the mucosa, intestine, lungs, and urinary system, and then moves to the vascular system. There are findings that the viral agent can prevent a host's innate immune system by NP activity [33]. Usually, when a microbe penetrates a host, the innate defense system detects the pathogen-associated molecular patterns (PAMPs) and aggravates the response of the immune system. One of the mechanisms identifies double-stranded RNA that is only produced by negative-sense viral agents [34]. In the cytoplasm, dsRNA receptors, such as melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-inducible gene I (RIG-I), detects dsRNAs and facilitates signaling pathways that results in the translocation of interferon regulatory factor 3 (IRF-3) and other transcription factors to the nuclear material [9]. Translocated transcription factors enhance expression of interferons and , and secreted interferons facilitate antiviral responses including adaptive immunity. NP encoded in the viral agent is important in the replication and transcription of the virus, but it also stops host innate IFN response by inhibiting translocation of IRF-3. NP of the virus is reported to have an exonuclease activity to only dsRNAs [12]. Double-stranded RNA exonuclease activity of the NP leads to counteract IFN responses by digesting the PAMP that leads to the evasion of host immune responses.

that died from hemorrhagic shock and multi-organ failure, the proinflammatory cytokines, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ) rises to extremely high level just before death. In a related study, no increase of both cytokine levels was reported in the checked fatal cases of the virus fever, and it is suggestive that the levels of IFN-γ and TNF-α are either elevated only in a fraction of patients or during a limited period that would involve

A Reemerging Lassa Virus: Aspects of Its Structure, Replication, Pathogenicity and Diagnosis

http://dx.doi.org/10.5772/intechopen.79072

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Virus-induced immunosuppression may be involved in a severe Lassa fever pathogenesis where the LASV infection fails to trigger macrophages (MP) and monocyte-derived dendritic cells (DC) of human. Human-infected DC with the naturally nonpathogenic mopeia virus, induces stronger CD4 and CD8 T-cell responses when compared with those infected with LASV [5, 8]. Infected DC fail to secrete proinflammatory cytokines, do not upregulate costimulatory molecules, such as CD40, CD80, and CD86, and poorly induce proliferation of T cells. Downregulation of immune responses due to infection by LASV has been depicted in vitro, and it is also in consonance with findings of clinical reports demonstrating that the virus fever fatal outcome relates with low

Different diagnostic tests in the laboratory are carried out in order to check the presence of an infection and assess its course and complications. The unavailability of lab tests can compromise diagnosis confidence. The most disturbing factor is the presence of febrile illnesses in Africa that mimics the Lassa fever, such as typhoid fever especially for manifestations of nonspecific Lassa fever [31]. In illness with abdominal pain, in countries where the virus is epidemic, Lassa fever may be misdiagnosed as intussusception and appendicitis that leads to delay in treatments with the antiviral drug (ribavirin) [37]. In West Africa, where the virus is most prevalent, it is difficult for laboratory scientists to diagnose due to the absence of the

The Federal Drug Administration (FDA) has not approved any widely validated laboratory test for the virus, but there are diagnostic tests, which have been able to provide definitive evidence of the presence of the virus [4, 14]. These tests include viral cultures, polymerase chain reaction (PCR) where the virus can be uncovered using reverse transcription PCR after first reverse transcribing the RNA of the virus into DNA, Enzyme Linked Immunosorbent Assay (ELISA) test, immunofluorescence test, and plaque neutralization. But, immunofluorescence tests give less definitive presence evidence of the viral presence. Other laboratory reports in the virus fever include thrombocytopenia, lymphopenia, and elevated aspartate aminotransferase levels in the blood. The viral agent can occasionally be present in cerebrospinal fluid [38, 39].

Viral isolation in cell culture remains the "gold standard" for the diagnosis of Lassa fever given the challenges in diagnosing the virus due to mutations [38], although RT-PCR and

levels interleukin (IL) 8 and IFN inducible protein 10 (IP-10) in the system [14].

frequent sampling for assay [12, 34].

**5. Aspect of Lassa virus diagnosis**

right equipment to perform the tests [4].

**5.1. Viral culturing**

The following diagnostic methods are briefly discussed below.

The recent understanding of the pathogenesis of the viral fever does not involve the chain of functions that take place during development of the disease state and leads to mortality of severed ill patients [35]. The high death and truly dramatic course of the disease state, the pathological findings do not give the bench that would explain the mechanism of disease progression and the cause of mortality by the viral agent [5, 8]. Development of the cellular immune response failure, which would control dissemination of LASV is indicated by high serum titers of the virus, together with dispersed replication in tissues and lack of neutralizing antibodies that could lead to the fatal Lassa fever development [6, 36]. Patients check physically after fever onset usually depicts facial oedema, bilateral conjunctival hemorrhages, purulent pharyngitis, and abdominal disorders [5]. Pathological changes physically may include pulmonary oedema, ascites, pleural effusions, and hemorrhagic signs in the gastrointestinal mucosa while examination under the microscope reveals splenic necrosis, hepatocellular necrosis, adrenocortical necrosis and apoptosis, mild mononuclear interstitial myocarditis without myocardial fiber necrosis, alveolar oedema with capillary blockage and mild interstitial pneumonitis, lymph nodal sinus histiocytosis with mitoses, gastrointestinal mucosal petechiae, renal tubular injury, lymph nodal sinus histiocytosis with mitoses, and interstitial nephri. More often, lesions of Lassa fever in man happen in the hepatic cells [5, 8]. There are four major characteristic hepatitis of LASV, which is derived:


The physical impacts do not happen uniformly in all cases, rather in some instances can be observed simultaneously.

The virus fever is not associated with coagulation dysfunction, for example, decrease in the coagulation factors and disseminated intravascular coagulation (DIC) have been revealed in infected subjects. More so, moderate thrombocytopenia with importantly damaged functionality of thrombocytes is reported in severe Lassa fever subjects [7, 36]. One significant mechanism involved in the pathogenesis of Lassa fever is infection-triggered induction of uncontrolled cytokine expression, which looks like what is seen in sepsis [9]. In this subject that died from hemorrhagic shock and multi-organ failure, the proinflammatory cytokines, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ) rises to extremely high level just before death. In a related study, no increase of both cytokine levels was reported in the checked fatal cases of the virus fever, and it is suggestive that the levels of IFN-γ and TNF-α are either elevated only in a fraction of patients or during a limited period that would involve frequent sampling for assay [12, 34].

Virus-induced immunosuppression may be involved in a severe Lassa fever pathogenesis where the LASV infection fails to trigger macrophages (MP) and monocyte-derived dendritic cells (DC) of human. Human-infected DC with the naturally nonpathogenic mopeia virus, induces stronger CD4 and CD8 T-cell responses when compared with those infected with LASV [5, 8]. Infected DC fail to secrete proinflammatory cytokines, do not upregulate costimulatory molecules, such as CD40, CD80, and CD86, and poorly induce proliferation of T cells. Downregulation of immune responses due to infection by LASV has been depicted in vitro, and it is also in consonance with findings of clinical reports demonstrating that the virus fever fatal outcome relates with low levels interleukin (IL) 8 and IFN inducible protein 10 (IP-10) in the system [14].
