MEDBULLETIN
CO MINI ISSUE MMEEDDUUCCAATTOORR | A PV RID L -21091 9
table of contents medbulletin section title
COVID-19 INFECTS BRAIN ORGANOIDS AD R I A N W O NG
NUR I SO N G
W hi le COV ID-19 is most k now n for causing respirator y i l lness, neurologica l sy mptoms have a lso a risen a mong infected pat ients. In Apri l, Mao et a l. repor ted t hat out of 214 pat ients in Wu ha n, China, 36.4% a lso suf fered f rom neurologica l ma nifestat ions. 1 These sy mptoms ca n ra nge f rom t he common headaches, dizziness, a nd loss of smel l or taste, to more severe condit ions such as acute ischemic stroke, encepha lit is, a nd Gui l la in-Ba rré sy ndrome. 2 Yet, to date, t he connect ion bet ween COV ID-19 infect ion a nd pat hologies of t he ner vous system rema ins incomplete.
Ev idence shows t hat a nosmia, or loss of smel l, is a prominent sy mptom of SA R S -CoV-2 . 1 Ident if ied as one of t he ea rliest signs of v ira l infect ion, a nosmia is present in 33.9% to 68% of sy mptomat ic ind iv idua ls, as fou nd by a nu mber of cross-sect iona l stud ies. 2 , 3 W hi le t he loss of smel l is a n accepted consequence of SA R S -CoV-2 , its pat hogenic mecha nism has been u nclea r u nt i l recent ly.
New resea rch f rom t he Universit y of Hong Kong has revea led t hat t he SA R S-CoV-2 v ir us ca n direct ly infect neurona l progenitor cel ls (NPCs) a nd bra in orga noids. W hi le NPCs may dif ferent iate into va rious neurona l cel l t y pes, bra in orga noids mimic t he str ucture a nd development of t he hu ma n bra in a nd have been used to understa nd how v ir uses ca n cause encepha lopat hy. 3,4 Zha ng et a l. f irst infected NPCs w it h SA R S-CoV-2 , using SA R S-CoV v ir us as a control. It was found t hat on ly SA R S-CoV-2 was capable of replicat ion in NPCs, a nd t hat t he qua nt it y of NPCs was reduced to 4.7% of its origina l va lue fol low ing SA R S-CoV-2 infect ion. 3 The resea rchers t hen infected a bra in orga noid w it h SA R S-CoV-2 a nd discovered signif ica nt a mounts of v ira l a nt igen 72 hours a f ter infect ion, indicat ing direct infect ion by t he v ir us.
Hy pot hesizing t hat t he loss of smel l in pat ients was due to t he binding of a ng iotensin-conver t ing enz y me 2 (ACE2) receptors by t he v ir us, resea rchers at Johns Hopk ins conducted a notable prelimina r y study mapping ACE2 receptors in nasa l t issue. 4 The study resu lts demonst rated a hig h concent rat ion of ACE2 receptors in t he olfactor y neuroepit heliu m. To obta in study f ind ings, Chen et a l. collected olfactor y epit heliu m a nd respirator y epit helia l sa mples f rom chronic rhinosinusit is pat ients a nd cont rol subjects. They conducted a n immu nohistolog ica l a na lysis, revea ling a hig h concent rat ion of ACE2 receptors on sustentacu la r cel ls, which a re a t y pe of st r uctura l nasa l cel l in t he olfactor y neuroepit heliu m. 5 It is li kely t hat SA R S -CoV-2 ta rgets t hese cel ls as a key point of ent r y into t he body, ex pla ining t he onset of a nosmia in t he ea rliest stages of infect ion. As a resu lt, Chen et a l. have suggested t hat when pat ients a re asy mptomat ic, t he olfactor y cel ls of t he nasa l t issue might be t he sing u la r site of infect ion.
The f indings of Zha ng et a l. have implicat ions for understa nding t he lin k bet ween COV ID-19 infect ion a nd its neurologica l ma nifestat ions, especia l ly by suggest ing t he possibi lit y of neurona l infect ion by SA R S-CoV-2. Addit iona l ly, t he infect ion a nd subsequent reduct ion of NPCs cou ld negat ively a f fect possibi lit ies of recover y. 3 Given t he increasing impor ta nce of t he neurologica l sy mptoms of COV ID-19 —especia l ly t he loss of smel l a nd taste —t hese f indings inv ite f ur t her resea rch into t he long-term impact of SA R S-CoV-2 infect ion on t he centra l ner vous system as wel l as neurologica l lyfocused treat ments. 3
The g iven f ind ings have va rious implicat ions for t herapeut ic approaches for COV ID-19. By helping to ex pla in t he ra nge of nasa la nd taste-related sy mptoms of COV ID-19, t he study has adva nced t he sea rch for t he best topica l or loca l a nt iv ira l dr ugs for COV ID-19, as wel l as ot her t herapeut ic approaches. W het her sa line irrigat ion, a common t reat ment for sinonasa l cond it ions, has potent ia l to mit igate spread of infect ion is st i l l u nclea r; however, a nt iv ira l dr ug add it ives such as detergent or pov idone iod ine d irected at nasa l v ira l reser voirs shou ld be f ur t her ex plored. 6
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COVID-19 AND ANOSMIA
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Image: Vaccarino Lab, Yale University. Research published in: (Amiri et al., Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science 362,2018)
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