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Curr Opin Virol. Author manuscript; available in PMC 2020 August 31.
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Published in final edited form as:

Curr Opin Virol. 2019 August ; 37: 118–122. doi:10.1016/j.coviro.2019.08.001.

Current Small Animal Models for LASV Hearing Loss

Rachel A. Sattlera, Junki Maruyamaa, Nathan Y. Shehub, Tomoko Makishimac, Slobodan
Paesslera,*
aDepartment of Pathology, University of Texas Medical Branch, 301 University Blvd., Galveston,
TX, USA, 77551-0609
bDepartment of Medicine, Infectious Disease Unit, Jos University Teaching Hospital, Jos, Plateau
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State, Nigeria
cDepartment of Otolaryngology, University of Texas Medical Branch, 301 University Blvd.,
Galveston, TX, USA, 77551-0609

Abstract
Lassa virus (LASV) is endemic in West Africa, causing an estimated 100,000-300,000 new
infections and up to 5,000-10,000 deaths yearly. There are no vaccines and therapeutics are
extremely limited. Typical case fatality rates are ~1%, although a recent 2018 Nigerian outbreak
featured an unprecedented 25.4% case fatality rate. Survivors of infection suffer a lifetime of
sequelae with sudden onset sensorineural hearing loss (SNHL) being the most prevalent. The
cause of this hearing loss remains unknown, and there is a critical need for further research on its
mechanisms and potential therapeutics. The objective of this review is to outline the only currently
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available small animal model for LASV-induced hearing loss and to identify potential surrogate
models.

I. Introduction
Lassa virus (LASV), a member of the Arenaviridae family, is the causative agent of Lassa
fever (LF) [1,2]. It is a negative-sense RNA virus with a bisegmented, single-stranded
genome [3]. LASV was first isolated in Nigeria from two missionary nurses who died from
LF in 1969 [1,2]. The virus is endemic throughout West Africa, but is especially prevalent in
Sierra Leone, Liberia, Guinea, and Nigeria [2]. Its natural host is the Mastomys natalensis
rodent; recent studies suggest the virus is also present in the M. erythroleucus and
Hylomyscus pamfi [2,4]. Exposure to humans typically occurs through the ingestion or
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inhalation of the excretions of infected rodents; person-to-person transmission occurs via

contact with infected bodily fluids, elevating the risk of nosocomial transmission during

*
Corresponding Author – Slobodan Paessler, Department of Pathology, University of Texas Medical Branch, 301 University Blvd.,
Galveston, TX, USA, 77555-0609, slpaessl@utmb.edu.
Declarations of Interest: None
Authors declare no conflict
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 Sattler et al. Page 2

outbreaks [2]. Current estimates place the number of new infections each year as high as
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100,000-300,000, with as many as 5,000-10,000 deaths from LF [2,5]. Case fatality rates are
typically around 1%, with this number elevated to 15-20% in hospitalized cases [2].
Alarmingly, the most recent 2018 Nigerian outbreak of LF featured an unprecedented 25.4%
case fatality rate, the cause of which remains unknown [6,7].

Symptom-onset typically occurs 1-3 weeks post infection [2]. 80% of cases are
asymptomatic, or present with mild, non-specific febrile symptoms, often leading to high
rates of misdiagnosis [1,2,8,9,10]. The other 20% of infections will progress to develop a
more severe hemorrhagic or neurologic disease [2]. Symptoms include disorientation,
respiratory distress, diarrhea, vomiting, abdominal pain, facial edema, severe pharyngitis,
encephalitis, hearing loss, tremors, and hemorrhage [1,2]. Pregnant women infected with
LASV have an elevated risk of death and of spontaneous abortion of their fetus [11]. Death
typically occurs around two weeks after onset of symptoms from multi-organ failure [2].
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Current treatments for patients are limited to the off-label use of ribavirin [2,12].
Unfortunately, ribavirin is only effective if administered within the first six days after
symptom onset and is extremely expensive [12,13]. Combined with the high rate of
misdiagnosis, this short time frame is difficult to meet [9]. Importantly, the use of ribavirin is
also associated with high rates of side effects requiring further medical intervention, such as
hemolysis [12]. There are no vaccines against the virus.

Survivors of infection often suffer life-long sequelae. One-third of survivors will develop
sudden onset sensorineural hearing loss (SNHL), which is permanent in two-thirds of cases
[5,14,15]. This hearing loss presents as unilateral or bilateral, may develop during the late
stage of disease or in early convalescence, and occurs even in subclinical cases [15].
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Treatment with ribavirin has not been shown to ameliorate or slow the progression of
hearing loss [15]. Recent studies indicate that this hearing loss may be autoimmune-
mediated, as opposed to being caused by direct damage from viral infection [16,17].
Moreover, SNHL is generating a huge socioeconomic burden in endemic countries [14].
Countries such as Nigeria are spending upwards of $43 million each year in aid programs
[14]. These countries also suffer from increased rates of depression and unemployment, due
to the isolation and stigmatization associated with hearing loss [18]. Children suffering from
SNHL are especially affected, being hindered by both social stigmatization and the lack of
rehabilitation services [18]. Alarmingly, LASV-induced SNHL is likely more prevalent than
current studies are aware. With 80% of cases being subclinical and undiagnosed, people may
suffer this hearing loss without ever identifying the cause; 18.3% of children with hearing
loss in Nigeria have reported an undiagnosed febrile illness [1,2,14,18].
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Understanding the mechanisms driving this hearing loss is vital for LASV vaccine and
therapeutic development. There are three main possibilities as to the mechanism behind
LASV-mediated hearing loss: damage from an immune response, direct viral damage, or a
combination of the two. Current research indicates that this hearing loss may be at least
partially driven by an autoimmune mechanism [16,17]. The STAT1−/− murine model
demonstrates inner ear damage that appears localized to various structures within the inner
ear, implicating a targeted immune response, possibly from autoimmunity, as the driving

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force behind LASV-mediated SNHL [16]. The non-human primate model implicates a
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systemic autoimmune-mediated vasculitis in the development of LASV-mediated SNHL

[17]. In both autoimmune scenarios, the host immune system would likely target the two
most immunogenic viral components, the glycoprotein (GP) or the nucleoprotein (NP). This
concept is alarming; current vaccine strategies target the most immunogenic components of
the virus. Thus, any developed vaccines risk inducing SNHL in recipients. Further research
into the mechanisms of this hearing loss is essential for safe vaccine development. However,
there is currently only one small animal model for LASV-induced hearing loss [16].
Studying LASV is severely hindered by the fact that the virus is a Select Agent Priority A
Pathogen that must be kept in BSL-4 facilities. The objective of this review is to outline the
details of the only small animal model currently available through which to study LASV-
mediated SNHL, as well as to identify potential surrogate models.
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II. LASV Murine Model

The only current small animal model for LASV-induced SNHL is the STAT1−/− mouse,
from a 129S6 background. In this model, among the STAT1−/− mice surviving 105 PFU of
either the lethal (LF2384) or nonlethal (LF2350) clinical isolates from the 2012 Sierra Leone
outbreak, 100% developed hearing loss [16]. With 104 PFU of virus, hearing loss will only
develop in around 20% of survivors [16]. Onset of hearing loss occurs between 16-45 dpi, as
measured by the Acoustic Startle Response (ASR) [16]. Ongoing studies are needed to
better characterize this SNHL, perhaps including analyses such as the Auditory Brainstem
Response (ABR) to assess the neuronal function of the entire auditory pathway and
Distortion Product Otoacoustic Emissions (DPOAE) testing, measuring auditory nerve
functionality to assess the cochlear hair cell function.
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Histological examination of the inner ear identified severe damage [16]. The spiral ganglion
neurons and cochlear nerve were significantly damaged, while the adjacent facial nerve
remained intact [16]. On the other hand, there was only minimal damage to the inner and
outer hair cells [16]. This localized damage indicates that this SNHL is immune-mediated
and thus targeted to specific regions of the inner ear. Other findings include significant
thinning of the stria vascularis, vacuolization of the spiral ganglion, distention of Reissner’s
membrane, and an infiltration of blood cells within the scala tympani [16]. Moreover, LASV
antigen was detected in the vascular-rich regions, colocalizing with a significant infiltration
of CD3+ lymphocytes [16]. This colocalization of CD3+ lymphocytes with both viral antigen
and cellular damage is further indication of immune-mediated damage. If immune-mediated
in origin, this SNHL would likely be generated by either cross-reactivity of the immune
response with an antigen found in the inner ear or by an immune-mediated activation of
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cellular stress pathways [19].

Interestingly, while infected STAT1−/− mice developed hearing loss, IFNαβ/γR−/− mice did
not; all IFNαβ/γR−/− surviving LASV infection maintained normal hearing [16]. This
difference is also seen in the inner ear histological examination; IFNαβ/γR−/− mouse
samples appear similar to those of the mock infected mice [16]. The genetic differences
between these strains provides further indication that LASV-mediated hearing loss is likely
driven by an immune response. The IFNαβ/γR−/− mice have no functional interferon

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pathways; the entire pathway is permanently silenced by non-functional receptors. STAT1−/−

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mice are affected further downstream of the receptors, also theoretically silencing the
pathway as STAT1 is unable to translocate to the nucleus and cause stimulation of its
interferon stimulated genes (ISG). However, while STAT1 is affected, STAT2 expression and
functionality remain intact. Upon stimulation of the interferon receptors, minimal amounts
of STAT2 are able to translocate to the nucleus and cause the induction of ISGs. Thus, this
strain of STAT1−/− mice are able to maintain a minimal antiviral response upon stimulation
of the interferon receptors. In the presence of this minimal interferon response, LASV-
infected STAT1−/− developed SNHL while the IFNαβ/γR−/− mice lacking an interferon
response do not, providing further indication the immune system is involved in LASV-
mediated SNHL.

III. ML29 Murine Model

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As previously mentioned, LASV is a BSL-4 pathogen, restricting access and studies,

especially those using animal models. In 2005, a live-attenuated vaccine candidate named
ML29 was developed for LASV [20]. ML29 was generated using the LASV S segment and
the L segment of Mopeia virus (MOPV), an arenavirus non-pathogenic to humans, and has
been shown to be more attenuated than MOPV in a STAT1−/− model [20,21]. As the primary
immunogenic factors of LASV, the GP and NP, are both contained in ML29, this vaccine
candidate may induce the same immune response as in LASV and thus induce hearing loss
in an identical mechanism. This is alarming from a vaccine perspective, and must be
addressed for continual development of ML29 as a LASV vaccine candidate. However, as
ML29 is attenuated and need not be used in a BSL-4 setting, using it as a surrogate model
for LASV-mediated hearing loss would allow for increased accessibility for further studies.
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Recent unpublished work demonstrated that wild-type 129S6 mice inoculated with 103 PFU
of ML29 do not develop hearing loss up to 8 weeks post-inoculation, as measured through
ASR, ABR, and DPOAE analysis. However, as these wild-type mice are not susceptible to
LF-like disease, further work is required to analyze this hearing loss in a STAT1−/− model
[16]. Developing this ML29 model to study LASV-driven SNHL would be extremely useful
for accessible mechanistic, vaccine, and therapeutic studies.

IV. Mechanistic Models of Virally Induced Hearing Loss in Rodents

Hearing loss induced by viral infections can be either acute and temporary or transition into
chronic and permanent. In an acute infection model, severe inflammatory responses to viral
infection can cause damage to cells within the ear, indirectly affecting auditory function. On
the other hand, chronic and gradual onset of hearing loss can be induced by an immune
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response. Two mechanistic models are of particular interest: 1) LPS transient hearing loss,
and 2) CMV-mediated hearing loss. Comparing these two models with our LASV model can
guide us to understand the mechanism of LASV-induced SNHL.

IV-1. LPS-Induced Transient Hearing Loss Model

Inner ear damage and the associated hearing loss has been correlated with a variety of viral
infections [22]. If localized to the upper respiratory tract, up to two-thirds of infections will

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result in hearing loss, be it conductive hearing loss alone or combined with sensorineural
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hearing loss, from acute otitis media [22]. Unresolved localized inflammation would allow
for damage to the inner ear eventually leading to sensorineural hearing loss. Acute otitis
media may be triggered by a bacterial infection that is a complication of the viral infection
[22]. As LASV-induced hearing loss is thought to be autoimmune-mediated [16,17], it is
possible that its onset may require an additional stimulus, such as a bacterial inner ear
infection. This would localize an immune response to the inner ear, where LASV antigen is
present [16], and allow for immune-mediated damage to occur to the inner ear. As a
mechanistic model for bacterial co-infections to the inner ear, transient hearing loss has been
successfully induced using the bacterial endotoxin lipopolysaccharide (LPS).

Previous work in Hartley guinea pigs demonstrated that LPS applied to the cochlea either
through the scala tympani or via injection into the cerebrospinal fluid results in hearing loss
within two hours [23,24]. This hearing loss is transient, and may be ameliorated by
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treatment with dexamethasone, an anti-inflammatory drug [23]. ABR analysis indicates a

temporary shift of as much as 30 dB in those guinea pigs suffering hearing loss, resolving to
near normal levels by 28 dpi [24]. Histologic analysis of the ear in this model confirms
damage to hair cells [23]. Additionally, the scala tympani and scala vestibuli feature a
marked infiltration of inflammatory cells, similar to what is noted in mice with SNHL after
LASV infection [16,24].

However, guinea pigs have not yet been shown to develop SNHL post-LASV infection. LPS
has been used in a mouse model to induce otitis media, although its effects on hearing have
not been extensively studied [25,26,27]. Although this model would require further
adaptation, LPS may be a triggering stimulus required to generate a reliable and accessible
Lassa-like SNHL model in survivors of both LASV and ML29 infections.
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IV-2. CMV-Mediated Hearing Loss

Cytomegalovirus (CMV) also causes SNHL in a manner likely to be at least partly due to the
immune response [28,29]. Moreover, similar to LASV, the hearing loss can develop in both
clinical and subclinical cases, presents as unilateral or bilateral, and varies widely in both
severity and time of onset [15,29]. Unlike with LASV, treatment with an antiviral has proven
to be effective in reducing CMV-mediated hearing loss in mouse models [15,30]. In LASV-
infected patients, administration of ribavirin is not correlated with a reduced incidence of
hearing loss, although it may help reduce disease severity [15]. The antiviral ganciclovir has
been shown to prevent hearing loss in CMV infection in mice [30].

CMV hearing loss is progressive; infected mice and guinea pigs feature a decline in hearing
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over four weeks, as confirmed by ABR and DPOAE analysis in mice and by ABR in guinea
pigs [28,30]. Histologic examination of the inner ears of infected guinea pigs indicates a
significant infiltration of inflammatory cells and fibrosis in the scala tympani [28,29].
Moreover, similar to LASV-induced SNHL, viral antigen is detected within the scala media,
Reissner’s membrane, organ of Corti, and the spiral ganglion [16,29]. Whether the presence
of the viral antigen triggers a cross-reactive response or the inflammatory response itself
causes the damage and its associated hearing loss remains unknown [29]. However, recent
studies indicate that the macrophage inducible protein 1-α (MIP 1-α), a pro-inflammatory

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cytokine released by CMV, is likely involved; knockout of this gene prevented the
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development of hearing loss in infected guinea pigs [28]. This knockout also features no
inflammatory cells or fibrosis present in the scala tympani, indicating that this MIP 1-α is
likely responsible for generating a localized immune response in the inner ear similar to that
seen in LASV-induced SNHL [28].

Having a surrogate virus small animal model that develops hearing loss in a similar fashion
to LASV-induced SNHL be helpful to future work. This model would be much more
accessible and easier to handle than the BSL-4 murine model, especially considering CMV
is a BSL-2 agent, allowing for testing of candidate interventions for those suffering hearing
loss. Future work should be conducted to compare CMV and LASV-mediated SNHL.

V. Conclusions
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The STAT1−/− murine model is the only currently available small animal model through
which to study LASV-induced SNHL. This model is markedly reproducible, with up to
100% of survivors developing hearing loss [14]. Moreover, the ability to house multiple
mice in one cage renders this model an excellent option for high containment animal studies.
However, the high containment requirements of LASV severely hinder research into both the
virus and its pathogenesis. Surrogate models of infection are of great importance. Being able
to mimic this hearing loss, perhaps using ML29, LPS, or CMV will provide much needed
insight to the mechanisms of LASV-induced SNHL, ultimately allowing for the development
of vaccines and therapeutics.

Acknowledgements
The authors apologize for works that we were unable to include in this review due to volume limitation. R.A.S. is
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funded by the Institute for Translational Sciences at the University of Texas Medical Branch, supported in part by
the Clinical and Translational Science Award NRSA (TL1) Training Core (TL1TR001440) from the National
Center for Advancing Translational Sciences at the National Institutes of Health. N.Y.S. is funded by
R01AI129198. S.P. and T.M. are partially supported by R01AI129198 from the National Institutes of Health.

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Main Concepts Discussed:

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• SNHL affects one third of LASV survivors, generating a huge socioeconomic

burden in endemic regions.

• The mechanism behind LASV-driven SNHL remains unknown, although it is

thought to be autoimmune-mediated.

• The only currently available small animal model to study LASV-mediated

SNHL is the STAT1−/− mouse.

• Future work is required to determine the application of transient LPS hearing

loss and CMV-mediated hearing loss for mechanistic studies of LASV-
mediated SNHL.
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Curr Opin Virol. Author manuscript; available in PMC 2020 August 31.