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\begin{document}

\title{Would STAT1 GOF prevent severe forms of COVID-19?}



\author[1]{Lara Teixeira}%
\author[2]{Carolina Aranda}%
\author[1]{Rafaela Guimarães}%
\author[1]{Luiza Schmid}%
\author[1]{Mariana Pimentel}%
\author[1]{Maria Rizzo}%
\author[3]{Ekaterini Goudouris}%
\author[2]{Dirceu Solé}%
\affil[1]{Federal University of Sao Paulo Allergy Clinical Immunology and Rheumatology Division}%
\affil[2]{Federal University of São Paulo}%
\affil[3]{Universidade Federal do Rio de Janeiro}%


\vspace{-1em}



  
  \date{May 10, 2024}


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Would STAT1 GOF prevent severe forms of COVID-19?

To the Editor:

As the world faces the current SARS-CoV-2 pandemic, the scientific
community struggles to answer questions about the disease that have not
been fully clarified yet. It is well known that individuals with certain
chronic diseases are at higher risk of having worse prognosis when
infected with this virus. Although the risk of a severe disease is still
a matter of conjecture in subjects with Inborn errors of Immunity (IEI),
these patients may present more COVID-19 complications than the general
population, either by community acquired or nosocomial
infection\textsuperscript{1}.

In our immunology referral clinic at the Federal University of S\selectlanguage{ngerman}ão Paulo
(UNIFESP), so far, 16 IEI patients have been diagnosed with COVID-19,
with a large spectrum of presentation, ranging from mild disease to
severe acute respiratory syndrome and death. One of them, however, had a
favorable outcome, with no complications, after being infected with the
SARS-CoV-2, despite his several serious comorbidities.

We report the case of an 11- year -old boy, diagnosed with Type 1
Diabetes Mellitus at the age of 3 years. At that time, he presented
persistent watery diarrhea, 3 to 4 episodes a day. One year later,
productive cough, persistent fever, conjunctival hyperemia and
generalized lymph node enlargement emerged. \emph{Histoplasma sp.} was
isolated in ocular secretion\emph{.} Acute Disseminated Histoplasmosis
(pulmonary, ocular and ganglionic) was diagnosed and he received
Itraconazole for one year.

In 2018, at the age of 9 years, we started to follow him at our
immunology clinic. He received all vaccines for his age with no adverse
events. The family reported recurrent skin infections, repeated
pneumonia, mucocutaneous and esophageal candidiasis, and arthralgia. He
presented hepatomegaly and failure to thrive. The main diagnostic
hypothesis was a disease of immune dysregulation. Screening for inborn
errors of immunity and inflammatory lab tests were performed. White
blood cell count, immunophenotyping and lymphocyte proliferation, serum
immunoglobulins and dihydrorodamine (DHR) assay were in normal range.
HIV serologies were negative. Whole exome sequencing was performed and
the variant c.1675G\textgreater{} C (\emph{de novo} variant) appeared in
the \emph{STAT1} gene (Figure 1)\textsuperscript{3}, in heterozygosis.
To date, no data on this genetic variant has been published. This new
finding is probably considered pathogenic and, due to the patient's
clinical characteristics, STAT1-GOF is very likely to be the diagnosis
of our boy.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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Figure 1

He was admitted to a pediatric hospital two weeks after his first
immunology appointment, due to exacerbation of respiratory symptoms. A
chest X-ray showed atelectasis in the apex of the right lung, already
observed in previous images. Chest tomography (CT) done at this time
showed extensive cylindrical bronchiectasis in the upper lobe of the
right lung. A group of thoracic surgeons recommended a lobectomy of the
right upper lobe for better control of recurrent lung infections. Figure
2 shows the chest CT performed nine months after surgery, during an
acute respiratory infection.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Treatment with a JAK inhibitor has been indicated, but it has not yet
been possible to start it.

Figure 2

In April 2020, the child was once again admitted to hospital,
complaining of dyspnea and chest pain for three days. His mother and
sister had fever and anosmia for a week, with positive RT-PCR for
SARS-CoV-2. He had no fever, cough or other respiratory symptoms.
Laboratory results showed leukopenia (3.280/\selectlanguage{greek}µ\selectlanguage{english}L) and positive RT-PCR for
SARS-CoV-2.

He was treated with inhaled salbutamol 800mcg/day, oral prednisolone
1mg/Kg/day, oral azithromycin 250mg/day and oral levofloxacin 250mg/day.
Oxygen saturation was above 95\% throughout the hospital stay, and
glycemic level was satisfactory with human insulin and strict monitoring
of a pediatric endocrinologist. Intraconazole prophylaxis was
maintained. After ten days of hospitalization, white blood cell count
went up to 9.710/uL. In addition, he presented D-dimer and interleukin 6
in the normal range (this last was 2.5, reference value less than 3.4
pg/mL). Chest CT did not show ground-glass opacities. Viral RNA load
determined by cell culture was present on the seventh day of symptoms.
At that same period, IgM against the novel virus was identified.

His nasopharyngeal swab for SARS-CoV-2 was still positive on the
13\textsuperscript{th} day of symptoms and became negative on the 16th
day, when antibodies that potentially neutralize SARS-CoV-2 were
identified. During all this period, he remained hospitalized, afebrile,
with no complaints and without supplemental oxygen.

SARS-CoV-2 is part of a large family of enveloped, single
positive-strand RNA viruses\textsuperscript{2}. When it enters the cell,
its RNA is recognized by the Toll-like-receptors (TLRs): 7/8 and 9 TLR.
The result is the activation of different signaling pathways and
transcription factors, resulting in the expression of genes, which
products are essential for antiviral and inflammatory responses. The 7/8
and 9 TLRs engage the MyD88 adapter leading to activation of the
transcription factor NFkB, which induces inflammatory responses. They
also signal via the TRIF adapter (TIR domain-containing adapter inducing
IFN-\selectlanguage{greek}β\selectlanguage{english}), that activates the interferon regulatory factor, which promotes
the production of type 1 interferons (IFN-\selectlanguage{greek}α / β\selectlanguage{english}), important for innate
antiviral immune responses\textsuperscript{4}.

Signal transducers and activators of transcription (STATs) are proteins
present in different cell types, involved in multiple functions of the
immune system \textsuperscript{4,5}. Mutations that lead to the gain of
function in STAT1 (STAT1-GOF) increase the uncontrolled phosphorylation
of this protein by impairing nuclear dephosphorylation. Thus, there is
greater production of STAT-dependent cytokines, such as type 1
interferon (IFN-\selectlanguage{greek}α / β\selectlanguage{english}) and interferon \selectlanguage{greek}γ \selectlanguage{english}(IFN-\selectlanguage{greek}γ\selectlanguage{english}). As already mentioned,
the first one has the role in virus defense, and the second helps to
fight mycobacteria. In addition, there is greater inhibitory effect on
the IL17 pathway\textsuperscript{4}.

Therefore, we have the hypothesis that despite the genetic
dysregulation, this patient may present some degree of protection
against a more severe form of COVID-19. Nonetheless, so far, there are
no reports of patients with STAT1-GOF infected with the novel
coronavirus in the world, which emphasizes the importance of continuing
research on this inflammatory syndrome, as well as on SARS-CoV-2
infection. The patient and his legal responsible consented to the case
report.

References

\begin{enumerate}
\tightlist
\item
  Shaker M, Oppenheimer J, Grayson M et al. COVID-19: Pandemic
  Contingency Planning for the Allergy and Immunology Clinic.~\emph{The
  Journal of Allergy and Clinical Immunology: In Practice} .
  2020;8(5):1477-1488.e5. doi:10.1016/j.jaip.2020.03.012
\item
  Raoult D, Zumla A, Locatelli F, Ippolito G, Kroemer G. Coronavirus
  infections: Epidemiological, clinical and immunological features and
  hypotheses.~\emph{Cell Stress} . 2020;4(4):66-75.
  doi:10.15698/cst2020.04.216
\item
  Reference G. \emph{STAT1} gene. Genetics Home Reference.
  https://ghr.nlm.nih.gov/gene/STAT1. Published 2020. Accessed September
  7, 2020.
\item
  Gaffen S. Structure and signalling in the IL-17 receptor
  family.~\emph{Nature Reviews Immunology} . 2009;9(8):556-567.
  doi:10.1038/nri2586
\item
  Hwa V. STAT5B deficiency: Impacts on human growth and
  immunity.~\emph{Growth Hormone \& IGF Research} . 2016;28:16-20.
  doi:10.1016/j.ghir.2015.12.006
\item
  Shi Y, Wang Y, Shao C et al. COVID-19 infection: the perspectives on
  immune responses.~\emph{Cell Death \& Differentiation} .
  2020;27(5):1451-1454. doi:10.1038/s41418-020-0530-3
\end{enumerate}

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